2,640 Matching Annotations
  1. Last 7 days
    1. 383T>C

      PatientID: 5

      KindredID: 5

      Case: F, 27Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: None. Sporadic

      CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

      CaseHPOFreeText: 'Other' phenotypes found in patient. These are noted in the paper to include: pancreatic neuroendocrine tumors (PNETs), renal and pancreatic cysts and central nervous system tumors, although it is not clearly stated that patient has all. (See Table 1).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L128P (c.383T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 1208816 https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L128P (c.383T>C)

      MultipleGeneVariants: N/A

    1. PatientID: III-9

      KindredID: 1

      Case: F, Age Unknown, Middle Eastern

      DiseaseAssertion: VHL

      FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

      CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009713; HP:0009711; HP:0006880 (hemangioblastoma; clear cell renal cell carcinoma; spinal hemangioblastoma; retinal capillary hemangioma; cerebellar hemangioblastoma)

      CaseHPOFreeText: Member had clear cell renal carcinomas in addition to hemangioblastomas. She had undergone multiple surgeries because of tumors involving the cerebellum, cervical spine, lumbar spine, multiple abdominal and pelvic organs and the retina. The tumor had been demonstrated on angiography as very extensive and vascular. The patient had had a partial nephrectomy, adrenalectomy, distal pancreatomy for involvement of the tail of the pancreas with a hemangioblastoma and a left salpingoophorectomy.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: Lacked evidence of any pheos.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W117C (c.351G>T)

      LegacyVariant: p.Trp117Cys (c.564G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    2. PatientID: III-8

      KindredID: 1

      Case: F, Age Unknown, Middle Eastern

      DiseaseAssertion: VHL

      FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

      CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009725; HP:0030692 (hemangioblastoma; clear cell renal cell carcinoma; bladder tumour; brain tumour)

      CaseHPOFreeText: Member had clear cell renal carcinomas in addition to hemangioblastomas. She was also the only member of the family to be diagnosed as having a bladder tumor, considered rare in VHL cases, and a brain tumor.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: Lacked evidence of any pheos.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W117C (c.351G>T)

      LegacyVariant: p.Trp117Cys (c.564G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    3. PatientID: III-7

      KindredID: 1

      Case: M, Age Unknown (deceased), Middle Eastern

      DiseaseAssertion: VHL

      FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

      CasePresentingHPOs: HP:0010797; HP:0006770 (hemangioblastoma; clear cell renal cell carcinoma)

      CaseHPOFreeText: Member had clear cell renal carcinomas that were the main cause of mortality, in addition to hemangioblastomas

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: Lacked evidence of any pheos.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W117C (c.351G>T)

      LegacyVariant: p.Trp117Cys (c.564G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    1. Missense VHL gene mutation Arg161Gln (695G-A) was found in two families

      PatientID: proband

      KindredID: 1

      Case: M, Age unknown, Chinese

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history as well as a confirmed presence of this same germline mutation in their family: sister and mother

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: Only non-syndromic pheochromocytomas were discussed here. See PMID: 20120764 for detailed information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

      CasePreviousTesting: N/A

      PreviouslyPublished: 20120764 - contains detailed family and patient information

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: p.R161Q (c.695G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    2. Leu163Phe (700C-T)

      PatientID: (proband)

      KindredID: 3

      Case: M, Age unknown, Chinese

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history, however their relatives were not available for the study. It is not perfectly clear which pedigree belongs to this family.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: non-syndromic pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L163F (c.487C>T)

      LegacyVariant: p.L163F (c.700C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 480772 https://www.ncbi.nlm.nih.gov/clinvar/variation/480772/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L163F (c.487C>T)

      MultipleGeneVariants: N/A

    3. Missense VHL gene mutation Arg161Gln (695G-A) was found in two families

      PatientID: (mother)

      KindredID: 2

      Case: F, Age unknown, Chinese

      DiseaseAssertion: unknown

      FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history as well as a confirmed presence of this same germline mutation in their daughter

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: p.R161Q (c.695G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. 21 missense mutations

      PatientID: 28

      KindredID: 288

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: One other member belonging to family 288 was mentioned (Patient: 5). This patient was found to have a pancreatic endocrine tumour and pheochromocytoma, without renal cell carcinoma.

      CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584 (renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. PatientID: III-23

      KindredID: 1

      Case: M, Age unknown, Ethnicity Unknown

      DiseaseAssertion: asymptomatic

      FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. His mom and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

      CasePresentingHPOs: None

      CaseHPOFreeText: VHL found by genetic testing not clinical findings.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E160Sfs*10 (c.477delA)

      LegacyVariant: c.688delA

      CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

      ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: E160fs (c.477del)

      MultipleGeneVariants: N/A

    2. PatientID: III-40

      KindredID: 1

      Case: F, Age unknown (deceased), Ethnicity Unknown

      DiseaseAssertion: asymptomatic

      FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. Her dad and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

      CasePresentingHPOs: None

      CaseHPOFreeText: VHL found by genetic testing not clinical findings.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E160Sfs*10 (c.477delA)

      LegacyVariant: c.688delA

      CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

      ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: E160fs (c.477del)

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: VHL 29

      DiseaseAssertion: assumed VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      GroupInfo: 2 patients with the given mutation belonging to VHL family 29

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

      GroupHPOFreeText: both (2) patients have retinal capillary hemangiomas, hemangioblastoma, and pheochromocytoma

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L178Q (c.533T>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L178Q (c.746T>A)

      ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: allele-specific oligonucleotide (ASO) probes and hybridization conditions confirmed

      MutationType: missense_variant; transversion

      CivicName: L178Q (c.533T>A)

      MultipleGeneVariants: N/A

    2. GroupID/ KindredID: VHL 32

      DiseaseAssertion: assumed VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      GroupInfo: 2 patients with the given mutation belonging to VHL family 32

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0000107; HP:0005584; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cyst, renal cell carcinoma, papillary cystadenoma of the epididymis)

      GroupHPOFreeText:  1 patient has retinal angiomas (retinal capillary hemangioma), 2 have CNS hemangioblastoma, 1 has renal cysts and renal cell carcinoma (RCC), 1 has pancreatic cysts, and one has cystadenomas of the epididymis (papillary cystadenoma of the epididymis).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161* (c.481C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R161* (c.694C>T)

      ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

      CAID: CA020408 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.481C%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: R161* (c.481C>T)

      MultipleGeneVariants: N/A

    3. GroupID/ KindredID: VHL 45

      Case: Sex unknown, Age unknown, German

      DiseaseAssertion: assumed VHL

      FamilyInfo: One patient with the given mutation is stated to belong to VHL family 45

      CasePresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.463+1G>C

      CaseProblemVariantFreeText: N/A

      LegacyVariant: 676+1G>C

      ClinVarID: 223217 https://www.ncbi.nlm.nih.gov/clinvar/variation/223217/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.463+1G>C)

      MultipleGeneVariants: N/A

    1. G93V (28) 1 

      GroupID:N/A

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 301 were enrolled to evaluate the natural history of vHL-associated pancreatic lesions. Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study.

      CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G93V (c.278G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625232 https://www.ncbi.nlm.nih.gov/clinvar/variation/625232/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:G93V(c.278G>T)

      MultipleGeneVariants: N/A

    2. D121Y (32) 1 

      GroupID:N/A

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 301 were enrolled to evaluate the natural history of vHL-associated pancreatic lesions. Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study.

      CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D121Y(c.361G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753754 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361G%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:D121Y(c.361G>T)

      MultipleGeneVariants: N/A

    1. KindredID:52

      GroupID: 6

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no.52 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: N/A

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: c.407C>T (p.S136L)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    2. KindredID: 21

      GroupID: 55

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no.21 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: No phenotypic information is listed for this kindred.

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q195* (c.583C>T)

      LegacyVariant: c.796C>T (p.Q266*)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428794, https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Q195* (c.583C>T)

      MultipleGeneVariants: N/A

    3. KindredID: 133

      GroupID: 23

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no. 133 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. No phenotypic information was available for this family.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: N/A

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114C (c.340G>T)

      LegacyVariant: p.G185C (c.553G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351751376; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114C (c.340G>T)

      MultipleGeneVariants: N/A

    1. c.239G>T [p.Ser80Ile]

      PatientID: Fetus 2 (of proband)

      KindredID: 9

      Case: Fetus, sex unknown, Chinese

      DiseaseAssertion: N/A

      FamilyInfo: Positive - Family history of RCC and Pheo; Parent had CNS hemangioblastoma presenting at 26Y. In prenatal diagnosis, two fetuses (1 & 2) were positive for the mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S80I (c.239G>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVar: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: S80I (c.239G>T)

      MultipleGeneVariants: N/A

    2. (c.233A>G [p.Asn78Ser]

      PatientID: 5

      KindredID: 5

      Case: 28Y0M, Sex unknown, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: None

      CasePresentingHPOs:  HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

      CaseHPOFreeText: CNS hemangioblastoma first presenting at age 28Y and RCC at age 28Y

      CaseNotHPOs: HP:0009715; HP:0002666 (Papillary cystadenoma of the epididymis, pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    3. PatientID: 4

      KindredID: 4

      Case: F, 52Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts)

      CaseHPOFreeText: Patient 4 was a 52-year-old female a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, retinal angioma, pancreatic cyst.

      CaseNotHPOs:None

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      LegacyVariant: c.446A>G

      CaseProblemVariantFreeText: N/A

      ClinVar: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: CA351749194

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_transition

      CivicName: N78S (c.223A>G)

      MultipleGeneVariants: N/A

    1. 7 c.239G>A p.Ser80Asn p.S80N Familial VHL

      PatientID: None

      KindredID: 7

      Case: Age, Sex, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Reported as familial VHL - no further information provided

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0002666; HP:0010797; HP:0001737; HP:0005584; HP:0000107 (pheochromocytoma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

      SupplementalData: N/A

      Variant: p.S80N (c.239G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 1070179 https://www.ncbi.nlm.nih.gov/clinvar/variation/1070179/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S80N (c.239G>A)

      MultipleGeneVariants: N/A

    2. 18 c.509T>A p.Val170Asp p.V170D Familial VHL

      GroupID/ KindredID: 18

      DiseaseAssertion: VHL

      GroupSize: 14

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 14 registrants belonging to the same family (18) have the germline VHL mutation.

      GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0000107; HP:0002666; HP:0030393; HP:0001407 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst, pheochromocytoma, endolymphatic sac tumor, hepatic cysts)

      GroupHPOFreeText: 6 had retinal hemangioblastoma, 9 had CNS hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, 5 had pancreatic cysts, 2 had endolymphatic sac tumors, 1 with adnexal papillary tumor of probably mesonephric origin, and 5 had hepatic cysts.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

      SupplementalData: N/A

      Variant: p.V170D (c.509T>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    3. 25 c.227_229delTCT p.Phe76del p.F76del Familial VHL

      GroupID/ KindredID: 25

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 2 registrants belonging to the same family (25) have the germline VHL mutation.

      GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, renal cell carcinoma)

      GroupHPOFreeText:  2 members with retinal hemangioblastomas and renal cell carcinoma, as well as 1 member with CNS hemangioblastoma

      GroupNotHPOs: HP:0001737; HP:0000107; HP:0002666 (pancreatic cysts, renal cyst, pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

      SupplementalData: N/A

      Variant: p.F76del (c.227_229delTCT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229delTCT)

      MultipleGeneVariants: N/A

    1. 1 France c.266T>C p.Leu89Pro

      GroupID: 7

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L89P (c.266T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    2. 1 France c.533T>C p.Leu178Pro

      GroupID: 34

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L178P (c.533T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    1. P3F2F12661nyOU20/250nn20/25nnn

      PatientID: 3

      KindredID: 2

      Case: F, 71Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: A family pedigree is provided. Patient’s daughter and granddaughter have the same mutation. Patient’s daughter had a retinal capillary hemangioma and lamellar macular hole in the left eye. The granddaughter did not seem to be affected.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The patient has tumours, but which she has were not specified (table 1).

      CaseNotHPOs: HP:0001737 (Retinal capillary hemangioma)

      CaseNotHPOFreeText: Patient did not have retinal capillary hemangiomas.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P192L (c.575C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 526677, https://www.ncbi.nlm.nih.gov/clinvar/variation/526677/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P192L (c.575C>T)

      MultipleGeneVariants: N/A

    1. c.357 C>Gap.F119L

      GroupID: 10A

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 2 VHL patients with the given VHL mutation and manifestation were grouped in this study.

      GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

      GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F119L (c.357C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: F119L (c.357C>G)

      MultipleGeneVariants: N/A

    2. c.266 T/Cap.L89P

      GroupID: 5A

      Case: Sex, Age, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

      CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L89P (c.266T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    3. c.482 G>Aap.R161Q

      GroupID: 22A

      DiseaseAssertion: VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 5 VHL patients with the given VHL mutation and manifestation were grouped in this study.

      GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

      GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    4. c.292 T>Cap.Y98H

      GroupID: 7B

      DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

      GroupSize: 158

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 158 patients with the given mutation were grouped as group 7(B) in this study. These patients were asymptomatic or unclear of symptoms.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: N/A

      GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

      GroupNotHPOFreeText: No recorded islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7987306

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. PatientID: V60

      KindredID: V60

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Four unaffected family members were tested and found to be negative. No other family history was available.

      CohortInfo:92 unrelated patients with VHL disease.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q(c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName:R161Q(c.482G>A)

      MultipleGeneVariants: N/A

    2. PatientID: V345

      KindredID: V345

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 92 unrelated patients with VHL disease.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: The patient was classified as VHL type 2B family meaning that she had a pheochromocytoma and presence of renal and pancreatic manifestations.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.C162W(c.486C>G)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:C162W(c.486C>G)

      MultipleGeneVariants: N/A

    3. GroupID: V31

      DiseaseAssertion: VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: Patients are grouped by family.

      FamilyInfo: 3/6 members of this family that underwent genetic testing had the same mutation.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: Diagnosed with VHL Type 1.

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573130363, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.531_532insCTGAGAGTAAAGCCTGAA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_insertion

      CivicName: L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

      MultipleGeneVariants: N/A

    1. PMID: 23143947

      PatientID: BII:6

      KindredID: B

      Case: M, 24Y0M (deceased), Chinese

      DiseaseAssertion: cerebellar hemangioblastoma

      FamilyInfo: A 3-generation family is given with 1 confirmed member tested for VHL (proband: III:5). His mother likely had the mutation as the mother and her brother both had VHL phenotypes at young ages (27Y and 22Y).

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient had operation for cerebellar hemangioblastoma at the age of 22 and died of bilateral multiple hemangioblastoma at the age of 24, with no chance of surgical treatment.

      CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584; HP:0001737 (retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, pancreatic cysts)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P154L (c.461C>T) [assumed]

      LegacyVariant: p.P154L (c.647C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 649525, https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this assumption

      MutationType: missense_variant; transition

      CivicName: P154L (c.461C>T)

      MultipleGeneVariants: N/A

    1. GroupID: 3575

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)

      GroupHPOFreeText: 2/3 members had retinal angiomas (hemangiomas), 1 had CNS hemangioblastoma and 1 had RCC

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N150Ifs*9 (c.448delA)

      CaseProblemVariantFreeText: NM_000551.3:c.448delA adjusts to up to date to NM_000551.4:c.449delA

      LegacyVariant: p.221fs (c.661delA)

      ClinVarID: 195093 https://www.ncbi.nlm.nih.gov/clinvar/variation/195093/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: N150fs (c.448delA)

      MultipleGeneVariants: N/A

    2. GroupID: 3624

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, renal cell carcinoma)

      GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040 (type 1 3624NCI)

      SupplementalData: N/A

      Variant: p.R176Gfs*26 (c.526delA)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R247fs (c.739delA)

      ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: R176fs (c.526del)

      MultipleGeneVariants: N/A

    3. GroupID: 3314

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, renal cell carcinoma)

      GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040

      SupplementalData: N/A

      Variant: p.L178P (c.533T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L249P (c.746T>C)

      ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    4. GroupID: 3786

      DiseaseAssertion: assumed VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

      GroupHPOFreeText: both (2/2) members had retinal angioma (hemangioma) and had CNS hemangioblastoma, and 1 had pheochromocytoma

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040

      SupplementalData: N/A

      Variant: p.L178P (c.533T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L249P (c.746T>C)

      ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    5. GroupID: 4480

      DiseaseAssertion: assumed VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

      GroupHPOFreeText: both (2) members had CNS hemangioblastoma, and 1 member had retinal angioma (hemangioma)

      GroupNotHPOs: HP:0002666; HP:0005584 (pheochromocytoma, renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V166D (c.497T>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L237D (c.710T>A)

      ClinVarID: 625254 https://www.ncbi.nlm.nih.gov/clinvar/variation/625254/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V166D (c.497T>A)

      MultipleGeneVariants: N/A

    6. GroupID: 2338

      DiseaseAssertion: assumed VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 4 family members recorded with this mutation.

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal cell carcinoma)

      GroupHPOFreeText: all 4 members had retinal angioma (hemangioma), 3 had CNS hemangioblastoma, 3 had pheochromocytoma, and 1 member had RCC

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040 (type 2 2338NCI)

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R238W (c.712C>T)

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 13

      KindredID: 6

      Case: F, Age unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The proband's daughter, patient 13, was asymptomatic at the time of the study.

      CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma )

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 115

      KindredID: 42

      Case: M, 12Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband (patient 42) had four family members confirmed with the mutation: his son (CNS hemangioblastoma at 12, retinal angioma at 11); his sister 1 (patient 116) presented with multiple pancreatic cysts/tumors at 53; his niece (daughter of sister 2) was asymptomatic at the time of assessment, and his nephew (son of brother 2) presented with a CNS hemangioblastoma at 12, and pheochromocytoma and multiple pancreatic cysts/tumors at 18. The proband also had three family members who passed away before diagnosis/ before they could be confirmed with the mutation: his sister 2 (patient 117) had multiple pancreatic cysts/tumors at 46, his brother 1 presented with a CNS hemangioblastoma at 47, renal cell carcinoma at 59, and multiple pancreatic cysts/tumors at 59; and his brother 2 presented with a retinal capillary hemangioma at 43, and CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 44.

      CasePresentingHPOs: HP:0010797; HP:0009711; (Hemangioblastoma, Retinal capillary hemangioma)

      CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 36, multiple pancreatic cysts and/or tumors at 40, and retinal angioma and renal cell carcinoma at 44.

      CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732; HP:0005584 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.W117G (c.349T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 862346; https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: W117G (c.349T>G)

      MultipleGeneVariants: N/A

    3. PatientID: 70

      KindredID: 24

      Case: F, 34Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband (patient no. 69) had the same germline mutation as his mother (patient no. 70). The proband himself presented with renal cell carcinoma at age 34, multiple pancreatic cysts/tumors at age 38, and pheochromocytoma at age 39.

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 34.

      CaseNotHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732; HP:0002666 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.W88* (c.263G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182978, https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: W88* (c.263G>A)

      MultipleGeneVariants: N/A

    4. PatientID: 237

      KindredID: 89

      Case: F, 46Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: The proband presented with renal cell carcinoma at age 46.

      CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0001737; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: c.642+70C>T

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 900551, https://www.ncbi.nlm.nih.gov/clinvar/variation/900551/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: 3'UTR alteration (c.*70C>T)

      MultipleGeneVariants: N/A

    5. PatientID: 30

      KindredID: 11

      Case: F, 37Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband (patient 30) has a son (patient 31) who was genetically confirmed with the mutation, who was asymptomatic at the time of analysis. She also has a father (patient 32, CNS hemangioblastoma at 42), a brother 1 (patient 33, CNS hemangioblastoma at 28), brother 2 (patient 34, CNS hemangioblastoma at 30), and uncle (patient 35, retinal angioma at 60) who passed away before they could be diagnosed/ genetically confirmed with the mutation.

      CasePresentingHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma)

      CaseHPOFreeText: The proband presented with CNS hemangioblastoma at 28, retinal angioma at 26, renal cell carcinoma at 37, and multiple pancreatic cysts/tumors at 28.

      CaseNotHPOs: HP:0002666 (Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.F76del (c.227_229del)

      LegacyVariant: F76del (c.224_226delTCT)

      CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

      ClinVarID: N/A

      CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.224_226delTCT)

      MultipleGeneVariants: N/A

    6. PatientID: 192

      KindredID: 73

      Case: F, 52Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband, patient 191, has a mother who was also found to have the same germline mutation. The proband's mother (patient 192) had a retinal angioma at 25, a CNS hemangioblastoma at 38, and multiple pancreatic cysts/tumors at 52.

      CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas)

      CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 38, retinal angioma at 25, and multiple pancreatic cysts/tumors at 52.

      CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.R167W (c.499C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    Tags

    Annotators

    URL

    1. 35 (45%) had missense variants

      PatientID: 7

      KindredID: 7

      Case: Age, Sex, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma

      CaseNotHPOs: HP:0030421; HP:0006770; HP:0100634; HP:0030405; HP:0009711 (epididymal tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm, pancreatic endocrine tumour, retinal capillary hemangioma)

      CaseNotHPOFreeText: patient was recorded without CCRCC, and a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), pancreatic endocrine tumour (or pancreatic neuroendocrine neoplasm), and a retinal hemangioblastoma, or a epididymal tumor

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    2. 35 (45%) had missense variants,

      PatientID: 49

      KindredID: 49

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

      CaseHPOFreeText: Recorded as a pheochromocytoma/paraganglioma

      CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.P154L (c.461C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 649525 https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P154L (c.461C>T)

      MultipleGeneVariants: N/A

    3. 86 VHL patients

      PatientID: 59

      KindredID: 59

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL (asymptomatic)

      FamilyInfo: N/A

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0009711; HP:0100634; HP:0030405; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma, Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.W88* (c.263G>A)

      LegacyVariant: p.W88* (c.476G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: W88* (c.263G>A)

      MultipleGeneVariants: N/A

    4. 35 (45%) had missense variants,

      PatientID: 3

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0006770; HP:0030405; HP:0009711; HP:0100634; HP:0030421 (clear cell renal cell carcinoma, pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Neuroendocrine neoplasm, Epididymal neoplasm)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.D92V (c.275A>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 184664 https://www.ncbi.nlm.nih.gov/clinvar/variation/184664/

      CAID: N/A

      gnomAD: 0.000004482 https://gnomad.broadinstitute.org/variant/3-10183806-A-T

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: D92V (c.275A>T)

      MultipleGeneVariants: N/A

    5. 35 (45%) had missense variants

      PatientID: 16

      KindredID: 16

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0100634; HP:0030421 (Neuroendocrine neoplasm, Epididymal neoplasm)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.P86L (c.257C>T)

      LegacyVariant: p.P157L (c.470C>T)

      CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted and confirmed this error. [from reported previously Aronoff et al, 2018].

      ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    6. 86 VHL patients

      PatientID: 58

      KindredID: 58

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL (asymptomatic)

      FamilyInfo: N/A

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0009711; HP:0100634; HP:0030405; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma, Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.W88* (c.263G>A)

      LegacyVariant: p.W88* (c.476G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: W88* (c.263G>A)

      MultipleGeneVariants: N/A

    7. missense variants

      PatientID: 64

      KindredID: 64

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0030405; HP:0009711; HP:0030421; HP:0006770 (hemangioblastoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma; Epididymal neoplasm, clear cell renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867 (Family 7 - see here for more info)

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.R107G (c.319C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: R107G (c.319C>G)

      MultipleGeneVariants: N/A

    8. 35 (45%) had missense variants,

      PatientID: 39

      KindredID: 39

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

      CaseHPOFreeText: patient had pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm)

      CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

      Variant: p.V84L (c.250G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V84L (c.250G>T)

      MultipleGeneVariants: N/A

    1. Disease-associated genetic abnormalities were identified in all of the seven families examined.

      PatientID: father

      KindredID: F

      Case: M, 53Y0M, Chinese

      DiseaseAssertion: assumed VHL

      FamilyInfo: Family history is said to be positive. Patient’s father had hemangioblastoma of the CNS at 23Y, and pancreatic cysts at 25Y.

      CasePresentingHPOs: HP:0010797; HP:0001737 (hemangioblastoma, pancreatic cysts)

      CaseHPOFreeText: Patient had hemangioblastoma of the CNS and pancreatic cysts diagnosed at 53Y

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q145* (c.433C>T)

      LegacyVariant: p.Q145* (c.646C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625249 https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Q145* (c.433C>T)

      MultipleGeneVariants: N/A

    1. 28a6Mc.353T>G2Missensep.Leu118Arg13P, mu, AP, H Asynchronous

      PatientID: 28

      KindredID: 6

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 2 members of this family, IDs #28 (13Y, M) and #29 (19Y, F) presented with the same variant and pheochromocytoma. Patient #28 also presented with head and neck as well as abdominal paraganglioma.

      CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

      CasePresentingHPOs: HP:0009711; HP:0002668 (Pheochromocytoma, Parganglioma)

      CaseHPOFreeText: Head and neck paraganglioma, abdominal paraganglioma and multifocal pheochromocytoma. 13Y at VHL diagnosis.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L118R (c.353T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428802, https://www.ncbi.nlm.nih.gov/clinvar/variation/428802/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: L118R (c.353T>G)

      MultipleGeneVariants: N/A

    1. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 13F, 564NCI, 1239NCI

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Neuro Olcologie database in Paris and the National Cancer Institute database, with an unknown number of members belonging to Family IDs 13F, 564NCI, 1239NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151; 9829911

      SupplementalData: N/A

      Variant: p.W117C (c.351G>T)

      LegacyVariant: p.W117C (c.564G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    2. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 1255NCI

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 1255NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151; 9829911

      SupplementalData: N/A

      Variant: p.W88R (c.262T>A)

      LegacyVariant: p.W88R (c.475T>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: W88R (c.262T>A)

      MultipleGeneVariants: N/A

    3. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 51CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 51CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E94* (c.280G>T)

      LegacyVariant: E94* (c.493G>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 584477 https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

      MutationType: stop_gained

      CivicName: E94* (c.280G>T)

      MultipleGeneVariants: N/A

    4. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 4389NCI, 1YO, 34CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, the Department of Uroglogy, Yokohama database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 4389NCI, 1YO, 34CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78H (c.232A>C)

      LegacyVariant: p.N78H (c.445A>C)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625225 https://www.ncbi.nlm.nih.gov/clinvar/variation/625225/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: N78H (c.232A>C)

      MultipleGeneVariants: N/A

    5. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 3315NCI, 127CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 3315NCI and 127CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151; 9829911

      SupplementalData: N/A

      Variant: p.S111N (c.332G>A)

      LegacyVariant: p.S111N (c.545G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: frameshift_variant; transition

      CivicName: S111N (c.332G>A)

      MultipleGeneVariants: N/A

    6. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 3786NCI

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3786NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

      GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

      GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151

      SupplementalData: N/A

      Variant: p.L178P (c.533T>C)

      LegacyVariant: p.L178P (c.746T>C)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    7. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 22YO

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 22YO. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S80Ifs*79 (c.239delG)

      LegacyVariant: FS (c.452delG)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA913189245 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239delG

      gnomAD: N/A

      VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

      MutationType: minus_1_frameshift_variant

      CivicName: S80fs (c.239delG)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 64

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: CNS hemangioblastoma.

      CaseNotHPOs: HP:0005584; HP:0009711; HP:0001732 (Renal cell carcinoma, Retinal capillary hemangioma, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86S (c.256C>T)

      LegacyVariant: c.469C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: 39

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseHPOFreeText: Retinal angioma.

      CaseNotHPOs: HP:0005584; HP:0001732; HP:0010797 (Renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 8634692

      SupplementalData: N/A

      Variant: p.P86L (c.257C>T)

      LegacyVariant: c.470C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    3. PatientID: None

      KindredID: 58

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: Renal cell carcinoma.

      CaseNotHPOs: HP:0010797; HP:0009711; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N90I (c.269A>T)

      LegacyVariant: c.482A>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223172, https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: N90I (c.269A>T)

      MultipleGeneVariants: N/A

    1. In family 9 in our series, we identified a VHL germline mutation(470 C>T, Pro86Leu) in a 53 years old woman (proband 9) with asynchronous bilateral renal clear cell carcinomas, multiple renal cysts and pancreatic cysts and with no positive family history, in her younger brother with a single phenotype (pancreatic cysts),and in her niece with no detectable VHL lesions. It is of interest that we find the same mutation in another unrelated VHL family (family 10) in which affected patients have severe phenotypes including multiple CNS haemangioblastoma, retinal angiomas, bilateral RCCs and pancreatic cysts. Compared with the family 10, it is very likely that the affected members in the family 9 will develop CNS haemangioblastoma and retinal angiomas in the future.

      PatientID: II-1 (proband)

      KindredID: 9

      Case: F, 53Y0M, Chinese

      DiseaseAssertion: assumed VHL

      FamilyInfo: Younger brother with a pancreatic cyst was mentioned. Her kids and grandkids (III-1, III-2, IV-1, IV-2, IV-3) were all tested for the VHL gene but found to be normal. Her niece was detected with the same mutation as her but with no detectable VHL lesions. [see Fig. 2].

      CasePresentingHPOs: HP:0005584; HP:0001737; HP:0000107 (Renal cell carcinoma, pancreatic cysts, renal cyst)

      CaseHPOFreeText: patient had bilateral renal clear cell carcinomas, multiple renal cysts and pancreatic cysts

      CaseNotHPOs: HP:0002666; HP:0010797; HP:0009711 (pheochromocytoma, hemangioblastoma, retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86L (c.257C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.P86L (c.470C>T)

      ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    2. The genotype and phenotype in the large Chinese family with VHL disease. a The pedigree of the family 6 with 18 affected patients. b DNA sequence analysis showing a A–G transition at nucleotide 446. The change results in the mutation from Asn to Ser in codon78.

      PatientID: IV-13

      GroupID/ KindredID: 6

      Case: Age unknown, M, Chinese

      DiseaseAssertion: asymptomatic

      FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, Renal cell carcinoma,abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

      LegacyVariant: p.N78S (c.446A>G)

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. In a family with VHL, we identified a novel missense mutation (N78D), which affects a fully conserved residue in the VHL protein. Interestingly, several other missense mutations reported at same codon in the VHL protein that might be associated with a low risk of renal cell carcinoma (RCC) but not pheochromocytoma appear to be associated with a VHL type 1 phenotype. At the moment, RCC is present in none of the affected mutation carriers in the family described here. In contrast to other missense changes at codon 78, the change in our VHL family is predicted to have a mild effect on VHL function, which apparently is insufficient to cause predisposition to RCC.

      PatientID: II-3

      KindredID: 1

      Case: F, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Reported 3 siblings (II:3, II:6, II:7) of a family clinically diagnosed as having VHL type 1 was identified with the c.232A>G mutation. Two female siblings (II:1, II:2) died from CHB. Three (II:3, II:6, II:7) of the ten siblings had multiple CNS haemangioblastomas, and all tested positive for the mutation. The age of onset for all patients varied from 20 to 25 years, and it was likely inherited from the mother who had died at the age of 40 years due to haemangioblastoma (in the medulla oblongata), and hydrocephalus after having multiple operations.

      CasePresentingHPOs: HP:0009713; HP:0006880; HP:0030393; HP:0001737; HP:0000107 (spinal hemangioblastoma, cerebellar hemangioblastoma; endolymphatic sac tumor; pancreatic cysts; renal cyst)

      CaseHPOFreeText: Patient presented with headache, tinnitus and abdominal pain. She had a history of endolymphatic sac tumors (ELSTs) treated by surgery. She had cerebellar/spinal haemangioblastomas, pancreas and kidney cystic masses.

      CaseNotHPOs: HP:0005584 (renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78D (c.232A>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625226 https://www.ncbi.nlm.nih.gov/clinvar/variation/625226/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: N78D (c.232A>G)

      MultipleGeneVariants: N/A

    1. GroupID: 39

      Case: 45Y0M, Sex Unknown, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

      CasePresentingHPOs: HP:0009711; HP:0006880; HP:0005584 (retinal capillary hemangioma; cerebellar hemangioblastoma; renal cell carcinoma)

      CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 45Y, cerebellar hemangioblastomas diagnosed at 24Y, and RCC at 45Y

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.K196Rfs*59 (c.584_585delAG) 

      LegacyVariant: N/A

      CaseProblemVariantFreeText: This mutation also automaps to NM_000551.3:c.585_586delGA

      ClinVarID: 547831 https://www.ncbi.nlm.nih.gov/clinvar/variation/547831/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift_variant

      CivicName: K196fs (c.584_585delAG)

      MultipleGeneVariants: N/A

    2. GroupID: 16

      DiseaseAssertion: assumed VHL

      GroupSize: 6

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 6 of the 573 patients discussed in this paper were found to have the following mutation belonging to 2 families.

      GroupPresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)

      GroupHPOFreeText: all 6 patients had retinal angiomas diagnosed at a mean age of 23Y, and 2 patients had cerebellar hemangioblastomas diagnosed at a mean age of 25Y.

      GroupNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma; pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.E94* (c.280G>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 584477 https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: E94* (c.280G>T)

      MultipleGeneVariants: N/A

    1. maternal aunts

      PatientID: IV-10

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The proband (V-5), his mother (IV-8), maternal grandmother (III-6), maternal aunts (IV-10, IV-12), cousin (V-9) and brother (V-6) were found to harbour the VHL mutation p.P86A (c.256 C>G). All were symptomatic of VHL except for his cousin.

      CasePresentingHPOs: HP:0010797; HP:0009711; HP:0030405 (Hemangioblastoma, Retinal capillary hemangioma, Pancreatic endocrine tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7728151(family 4416); 20375333

      SupplementalData: Information obtained from Figure 1.

      Variant: p.P86A (c.256 C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: P86A (c.256C>G)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 1

      Case: M, 2Y0M, Danish

      DiseaseAssertion:Asymptomatic

      FamilyInfo: The patient's father had the p.P2P VHL mutation as well as another VHL mutation (p.P81S) and presented with renal cell carcinoma. The patient's uncles had this p.P81S mutation but were both asymptomatic. The patient's paternal grandmother also had this mutation and had breast cancer. See Figure 1 for family pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText:N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P2= (c.6C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 456593 https://www.ncbi.nlm.nih.gov/clinvar/variation/456593/

      CAID: N/A

      gnomAD: 0.000 https://gnomad.broadinstitute.org/variant/3-10183537-C-G

      VariantEvidence: N/A

      MutationType: synonymous_variant

      CivicName: P2= (c.6C>G)

      MultipleGeneVariants: N/A

    1. A 1 0-year-old boy was admitted to our hospital with complaints of headache and diplopia. On physical examination, he weighed 40 kg (7590p), with a height of 142 cm (50-75p). His brachial blood pressure was 150/120 mmHg (95th percentile 123/81 mmHg). His mother had been operated for bilateral pheochromocytoma at the age of 23 and had not been under medical follow-up since then. Laboratory tests showed elevated 24-hour (h) urinary vanillylmandelic acid (VMA) (40 mg/day; normal value 1-11) and normetanephrine (>2000 µg/day), but normal metanephrine levels (143 µg/day). Abdominal magnetic resonance imaging (MRI) indicated the presence of multiple lesions in perivascular areas neighboring both adrenal glands. An iodine 123 metaiodobenzylguanidine (MIBG) scan revealed multiple focal areas of increased uptake near the adrenal glands. After the preparation for operation, bilateral subtotal adrenalectomy including removal of the masses was performed. The diagnosis of bilateral pheochromocytoma was confirmed histologically and immunohistochemically. The patient remained asymptomatic with no laboratory or radiologic abnormalities for six years of follow-up. At the age of 16, the patient was referred to our clinic with visual defect in the left eye. Ophthalmologic examination led to the diagnosis of bilateral retinal hemangiomas, and he underwent laser photocoagulation. Positive family history with bilateral pheochromocytoma and retinal hemangioma revealed the diagnosis of VHL disease. Cerebral, spinal MRI and abdominal computed tomography (CT) were normal.

      PatientID: Proband

      KindredID: 1

      Case: M, 10Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Mother was found with the same VHL germline variant. His mother presented with bilateral pheochromocytoma.

      CasePresentingHPOs: HP:0002315; HP:0000651; HP:0002666; HP:0009711; HP:0000822 (Headache, Diplopia, Pheochromocytoma, Retinal capillary hemangioma, Hypertension)

      CaseHPOFreeText: Admitted with complaints of headache and diplopia. MRI indicated the presence of multiple lesions in perivascular areas neighboring both adrenal glands. An iodine 123 metaiodobenzylguanidine (MIBG) scan revealed multiple focal areas of increased uptake near the adrenal glands. The diagnosis of bilateral pheochromocytoma was confirmed histologically and immunohistochemically. The patient remained asymptomatic with no laboratory or radiologic abnormalities for six years of follow-up. At the age of 16, the patient was referred to our clinic with a visual defect in the left eye. Ophthalmologic examination led to the diagnosis of bilateral retinal hemangiomas, and he underwent laser photocoagulation.

      CaseNotHPOs: HP:0009713; HP:0006880 (Spinal hemangioblastoma, Cerebellar hemangioblastoma)

      CaseNotHPOFreeText: Cerebral, spinal MRI and abdominal computed tomography (CT) were normal.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: c.695G>A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant was reported as “c.695G>A” which was mapped to p.Arg161Gln (c.482G>A) in accordance with reference sequence NM_000551.3.

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. IV2(A002)−−−−−Female

      PatientID: (IV2)A002

      KindredID: A

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Patient’s father possessed the same variant and presented with a CNS hemangioblastoma, clear cell renal cell carcinoma and pancreatic cystic disease. As well, patient’s paternal grandmother, two granduncles, and grandaunt-in-law had hemangioblastomas and are not longer alive. Proband's uncle also had a hemangioblastoma (please see figure 1 for pedigree).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0001737; HP:0002666; HP:0009919; HP:0006770 (Hemangioblastoma; pancreatic cysts; pheochromocytoma, retinoblastoma, Clear cell renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86S (c.256C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant reported as GRCh37 chr3:10183787C>T in paper; individual is a T homozygote

      MutationType: missense_variant; transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    1. c.263G>A p.Trp88Stop

      PatientID: None (proband 11)

      KindredID: 11

      Case: M, 38Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Patient’s mother (last known age 36Y) had a CNS hemangioblastoma diagnosed at 36Y.

      CasePresentingHPOs: HP:0005584; HP:0001737 (renal cell carcinoma, pancreatic cysts)

      CaseHPOFreeText: RCC and multiple pancreatic cysts or tumors diagnosed at age 34 and 38Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 22357542

      SupplementalData: N/A

      Variant: p.W88* (c.263G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: W88* (c.263G>A)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: VHL22

      Case: M, 40Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: The patient had one benign pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHC/SDHD

      PreviouslyPublished: N/A

      SupplementalData: Table 1 of Supplementary

      Variant: p.L178P (c.533T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: The patient had LOH found in the BAC array CGH data.

      MutationType: missense_variant;transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: VHL23

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: The patient had one malignant pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHC/SDHD

      PreviouslyPublished: N/A

      SupplementalData: Table 1 of Supplementary

      Variant: p.L178P (c.533T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: The patient had LOH found in the BAC array CGH data.

      MutationType: missense_variant;transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    1. Case 1: Clinical historyA 25-year-old woman presented with a 1-year history of slowly progressive and gradual decrease in hearing. Two years previously, the patient had undergone brain surgery because of hemangioblastoma of the cerebellum. Gene analysis performed at that time showed mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu). On physical examination, she was found to have a middle ear mass that protruded into the external auditory canal. Bone destruction was found radiographically. At surgery, vascular tumor tissue and cysts were seen permeating and destroying the adjacent petrous portion of the temporal bone with invasion of the mastoid and the semicircular canal. The patient underwent a complete removal of the tumor from the middle ear, mastoid, and petrous bone. However, recurrent destructive tumor of the middle ear appeared after 26 months.Family historyThe family medical history disclosed the presence of symptoms of VHLD in the patient's grandfather, uncle, and father. In particular, the patient's father presented with multi-tumor syndrome and evidence of genetic VHLD due to causal mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu). At the age of 30, he was operated on for cerebellar hemangioblastoma, and died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases 13 years later at the age of 43.

      PatientID: 1

      KindredID: 1

      Case: F, 25Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: The family medical history disclosed the presence of symptoms of VHLD in the patient’s grandfather, uncle, and father. In particular, the patient’s father presented with multi-tumor syndrome and a confirmed genetic mutation of c.194C>T. The father died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases at the age of 43.

      CasePresentingHPOs: HP:0006880;HP:0030393 (cerebellar hemangioblastoma, endolymphatic sac tumour)

      CaseHPOFreeText: Woman presented with slowly progressive and gradual decrease in hearing (beginning at 24Y). At 23Y the patient had undergone brain surgery because of hemangioblastoma of the cerebellum. Physical examination revealed a middle ear mass that protruded into the external auditory canal (recurrent restrictive tumor)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: genetic tests on tissue but suspected germline because father had same mutation, and 2 different tissue samples had same mutation; grandfather and uncle had VHL symptoms but not specified and no genetic confirmation

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. GroupID: 10

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 41 non-related patients with retinal angiomatosis between 1988 and 1999 were evaluated.

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.N78S (c.446A>G)

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. X214C one case (male)

      PatientID: None

      KindredID: 3

      Case: M, 62Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666; HP:0010797; HP:0009713; HP:0009711; HP:0006770; HP:0030405 (Pheochromocytoma, CNS hemangioblastoma, spinal hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, pancreatic endocrine tumour)

      CaseHPOFreeText: The patient presented with clear cell renal carcinoma, and a pancreatic neuroendocrine tumor at age 62. The patient also presented with bilateral pheochromocytomas, multiple CNS and spinal hemangioblatomas, and retinal hemangioblastomas at an unknown age.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.*214Cext*14(c.642A>T)

      LegacyVariant: N/A

      ClinVarID: 625270, http://www.ncbi.nlm.nih.gov/clinvar/variation/625270

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_loss

      CivicName: *214Cext*14(c.642A>T)

      MultipleGeneVariants: N/A

    1. Somatic 1a 1 c.163delG Stop at V66 Known 

      PatientID: HGB-25

      KindredID: 6

      Case: Sex Unknown, 61Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: Positive VHL family history.

      CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29941223

      SupplementalData: N/A

      Variant: p.E55Rfs*12 (c.163delG)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID:428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType:minus_1_frameshift_variant

      CivicName:CivicName:P25L(c.74C>T)andD126Rfs*6(c.375_376insA)andE55Rfs(c.163delG)

      MultipleGeneVariants: Somatic, VHL, c.375insA (Asn131Ter) Germline, VHL, c.74C>T (p.Pro25Leu)

    1. only one patient, with an atypical clinical presentation, had an aberrant pattern in exon 3 which upon DNA sequencing was shown to harbor a G to A transversion mutation at nucleotide 695. All patients had normal RET exon 10, 11 and 16 DGGE migration patterns.

      PatientID: N/A

      KindredID: 1

      Case: M, 34Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: None - Neither the symptoms nor a family history of VHL disease were found in the patient.

      CasePresentingHPOs: HP:0002668; HP:0002666 (bilateral metachronous pheochromocytoma; paraganglioma)

      CaseHPOFreeText: The first tumor occurred at age 13 and the second at age 34 (inferred from Table 1 as this was the only case with a bilateral metachronous).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: R161Q (c.695G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. PatientID: None (Proband)

      KindredID: 1

      Case: F, 49Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Her daughter and son both had the same VHL gene mutation.

      CasePresentingHPOs: HP:0008261, HP:0005584, HP:0006737, HP:0100561 (Pancreatic islet cell adenoma, renal cell carcinoma, Extraadrenal pheochromocytoma, spinal cord lesion )

      CaseHPOFreeText: The patient was screened for disease manifestations. Abdominal magnetic resonance imaging (MRI) and computerized tomography (CT) showed pancreatic and renal masses and a para-aortic mass. At laparotomy a benign islet cell tumor, an encapsulated renal cell carcinoma of low nuclear grade and an extra-adrenal pheochromocytoma were removed. At 27 months postoperatively the patient presented with back pain and clinical signs of spinal cord compression at the T9 level. No other primary tumors could be detected despite extensive radiological investigation. Intravertebral biopsy demonstrated metastatic renal cell cancer. The spinal lesion did not respond to radiotherapy. The patient died 31 months after diagnosis and postmortem examination was declined.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86L (c.257C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    1. Details of the specific mutation for each VHL patient, together with the physical characteristics of patients and control participants, are given in Supplemental Table S1.

      PatientID: 4

      KindredID: 4

      Case: F, 53Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Free from any associated neoplasia at the time of the study and no other medical disorders.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Table S1 (FormentiF VHLHIF2 SuppData1.pdf)

      Variant: p.S111N (c.332G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223186, https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S111N (c.332G>A)

      MultipleGeneVariants: N/A

    1. 4 Missense p.(Asn78Ser) 1 0

      GroupID: 4

      DiseaseAssertion: VHL

      Group size: 1

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. 

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Chr3(GRCh37): g.10183764A>G

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. 16-year-old girl with VHL consisting of retinal and CNS HBs and pancreatic cysts

      PatientID: II-a

      KindredID: 1

      Case: F, 16Y0M, Greek

      DiseaseAssertion: Assumed VHL

      FamilyInfo: The patient’s 50-year-old father has VHL consisting of retinal HBs diagnosed at the age of 20 years. He also has spinal cord HBs located in the neck. He was also found to carry the mutation NM_000551.3:c.433C>T that the patient carried. The patient’s 18-year-old brother and her 20-year-old sister are phenotypically healthy and repeated biochemical evaluation and imaging studies are negative. Her paternal uncle, aunt and cousins are also phenotypically healthy with no indications from either biochemical or imaging studies as they denied further evaluation. In addition, her paternal grandfather of unknown genotype died at the age of 85 years while her paternal grandmother is alive and has no problems, being 86 years old at time of writing.

      CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0001737 (Spinal hemangioblastoma, cerebellar hemangioblastoma, retinal hemangioblastoma, pancreatic cyst)

      CaseHPOFreeText: The 16Y female patient first presented with back pain, headaches, numbness, dizziness, weakness and pain in the arms and the legs at 12Y. A hemangioblastoma in the thoracic spine and a hemangioblastoma in the neck were found. A year later, at the age of 13, multiple HBs in the right and smaller lesions in the left eye were found. Two asymptomatic cysts (2 cm and 0.8 cm) in the body of the pancreas were also found. During her recent evaluation, at the age of 16 years, MRI imaging revealed a large HB extending from the cerebellum to the Th8 vertebrae, with extensive solid and cystic nodules inside the mass and increased dimensions of the spinal cord.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q145*(c.433C>T)

      LegacyVariant: N/A

      ClinVarID: 625249, https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

      gnomAD: N/A

      VariantEvidence: It has been documented that dynamic organisation of pVHL–HIF1α recognition is focally centred on Gln145 within the L7 loop, and its tumourigenic mutant Q145H abolishes almost all of the correlated dynamic motions. In this report, Q145 is substituted by a stop codon, p.Q145X. This is a nonsense mutation resulting to a truncated VHL protein that lacks the last 68 amino acids and thus its function is abolished.

      MutationType: stop_gained

      CivicName: Q145*(c.433C>T)

      MultipleGeneVariants: N/A

    1. 214Y4Y20NNNYNC.340G.AExon 1p.Gly114SerMissense

      PatientID: 2

      KindredID: 1

      Case: M, 20Y0M, Brazilian (Latino/Admixed American)

      DiseaseAssertion: VHL

      FamilyInfo: Also belonging to family 1, patients 1 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

      CasePresentingHPOs: HP:0006748, HP:0002666; HP:0030405; HP:0010797 (adrenal pheochromocytoma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

      CaseHPOFreeText: The patient developed PPGL at 4Y of age, and a PNET at 20Y: the 4-year-old boy with VHL disease with a history of sudoresis, headache, and abdominal pain. During evaluation, he was diagnosed with hypertension. An abdominal CT scan revealed a 5-cm heterogenous mass in the right adrenal and normal left adrenal glands. This patient underwent a right nodulectomy to preserve normal adrenal tissue. Anatomopathological diagnosis confirmed PHEO. 3 years later was a bilateral recurrence (4-cm right and 1.5-cm left nodules). The patient underwent a right-side adrenalectomy and a left-side nodulectomy. He remained without hormone replacement. After 13 years from the second surgery, the boy presented with a left-side recurrence (1.3-cm nodule) and elevated plasmatic normetanephrine levels; he underwent left-side adrenalectomy.

      CaseNotHPOs: HP:0005584; HP:0009711; HP:0001737; HP:0000107 (renal cell carcinoma, retinal capillary hemangioma, pancreatic cyst, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114S (c.340G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G114S (c.340G>A)

      MultipleGeneVariants: N/A

    2. 1138Y38Y38NNNNNc.340G>AExon 1p.Gly114SerMissense

      PatientID: 1

      KindredID: 1

      Case: Sex Unknown, 38Y0M, Brazilian (Latino/Admixed American)

      DiseaseAssertion: VHL

      FamilyInfo: Also belonging to family 1, patients 2 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

      CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor)

      CaseHPOFreeText: The patient developed PPGL at 38Y of age, and a PNET at 38Y.

      CaseNotHPOs: HP:0010797; HP:0005584; HP:0009711; HP:0001737; HP:0000107 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pancreatic cyst, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114S (c.340G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G114S (c.340G>A)

      MultipleGeneVariants: N/A

    3. 271910Y10N—NNNNNc.371C>TExon 2p.Thr124IleMissense

      PatientID: 27

      KindredID: 19

      Case: M, 14Y0M, Brazilian (Latino/Admixed American)

      DiseaseAssertion: VHL

      FamilyInfo: They had a 47Y family member (ID:26), however their relation is unclear.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: The patient at 10Y was confirmed with VHL. He developed bilateral pheo at 10Y with recurrence 48M later.

      CaseNotHPOs: HP:0002668; HP:0001737; HP:0010797; HP:0005584; HP:0030405; HP:0009711; HP:0000107 (paraganglioma, pancreatic cyst, hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumor, retinal capillary hemangioma, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.T124I (c.371C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 36902 https://www.ncbi.nlm.nih.gov/clinvar/variation/36902/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: T124I (c.371C>T)

      MultipleGeneVariants: N/A

    1. GroupID: 5

      Case: M, Age unknown, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

      CaseHPOFreeText: Other manifestations may be present although not matched with individuals so could not deduce.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W88R (c.262T>A)

      LegacyVariant: p.W88R (c.475T>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: W88R (c.262T>A)

      MultipleGeneVariants: N/A

    2. GroupID: 9

      Case: M, Age unknown, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: Unknown

      CaseHPOFreeText: Other manifestations may be present although not matched with individuals so could not deduce.

      CaseNotHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R176Gfs*26 (c.526del)

      LegacyVariant: p.R176Gfs*26 (c.739delA)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: Minus_1_frameshift_variant

      CivicName: R176Gfs (c.526del)

      MultipleGeneVariants: N/A

    1. GroupID: 503

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 2 members of this family presented with germline variants c.256C>T of the VHL gene. Member 10602 presented with moderate renal disease (RCC) and member 10603 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

      GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.P86S (c.256C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 5730

      KindredID: 269

      Case: Sex Unknown, Age Unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 1005.

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.L188P (c.563T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L188P (c.563T>C)

      MultipleGeneVariants: N/A

    3. PatientID: 5299

      KindredID: 235

      Case: Sex Unknown, Age Unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      CasePresentingHPOs: HP:0009726 (Renal neoplasm)

      CaseHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Individual RCC phenotype is noted as negative.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with an equivalent mutation (i.e. 473insT) are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.K159Efs*15 (c.473dup)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432423097, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.473dup

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: duplication; plus_1_frameshift_variant

      CivicName: K159Efs*15 (c.473dup)

      MultipleGeneVariants: N/A

    4. GroupID: 17

      DiseaseAssertion: VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 5 members of this family presented with the c.485G>A germline variant of the VHL gene. Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

      GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.C162Y (c.485G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: C162Y (c.485G>A)

      MultipleGeneVariants: N/A

    5. GroupID: 77

      DiseaseAssertion: VHL

      GroupSize: 13

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 13 members of this family were found to harbor the c.286C>T germline variant of the VHL gene. Members 5314, 6288, 6290, 5228 and 2499 had unknown renal involvement. Patients 5226, 6293 and 5340 presented with severe renal disease (RCC). Member 666 and 5223 presented with moderate renal disease (RCC). Members 5808 and 6380 had no renal involvement. Member 6277 presented with mild renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

      GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 3 individuals with this mutation are reported but relation between patients and to this patient is unknown.

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.Q96* (c.286C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition; stop_gained

      CivicName: Q96* (c.286C>T)

      MultipleGeneVariants: N/A

    1. F8c.340+617C>G + c.340+648T>C†/WTX1 p.Leu128Val+ X1 p.Leu138Pro/WTNNNNVHL disease—

      PatientID: I.2

      KindredID: F8

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

      CasePresentingHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma)

      CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+648T>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

      MutationType: missense_variant;transition; splice_site_variant

      CivicName: c.340+617C>G and c.340+648T>C

      MultipleGeneVariants: Germline, VHL, c.340+617C>G

    2. F8c.340+617C>G + c.340+648T>C†/WTX1 p.Leu128Val+ X1 p.Leu138Pro/WTNNNNVHL disease

      PatientID: II.6

      KindredID: F8

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseHPOFreeText: Presented with retinal capillary hemangioma. Tumor detected at age 16.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+648T>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 827583, https://www.ncbi.nlm.nih.gov/clinvar/variation/827583/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

      MutationType: missense_variant;transition; splice_site_variant

      CivicName: c.340+617C>G and c.340+648T>C

      MultipleGeneVariants: Germline, VHL, c.340+617C>G

    3. F3, II.1c.598C>T/c.340+770T>CVHL p.Arg200Trp/X1 p.Ser179Pro?2003/4 moM17.9547.560

      PatientID: II.1

      KindredID: 3

      Case: M, 0Y4M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: The patient had an affected brother (II.2) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

      CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

      CasePresentingHPOs: HP:0001901 (Polycythemia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+770T>C

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 816685 https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

      CAID: N/A

      gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

      VariantEvidence: N/A

      MutationType: intron_variant

      CivicName: c.340+770T>C and R200W (c.598C>T)

      MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

    4. F8c.340+617C>G + c.340+648T>C†/WTX1 p.Leu128Val+ X1 p.Leu138Pro/WTNNNNVHL disease—

      PatientID: I.2

      KindredID: F8

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

      CasePresentingHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma)

      CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+617C>G

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

      MutationType: missense_variant;transversion; splice_site_variant

      CivicName: c.340+617C>G and c.340+648T>C

      MultipleGeneVariants: Germline, VHL, c.340+648T>C

    5. F2, II.1c.598C>T/c.340+770T>CVHL p.Arg200Trp/X1 p.Ser179Pro?1957/21 yM19.96722.2Erythrocytosis—

      PatientID: II.1

      KindredID: 2

      Case: M, 21Y0M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: Positive family history. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

      CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state

      CasePresentingHPOs: HP:0001901 (Polycythemia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+770T>C

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 816685 https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

      CAID: N/A

      gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

      VariantEvidence: N/A

      MutationType: intron_variant

      CivicName: c.340+770T>C and R200W (c.598C>T)

      MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

    6. F3, II.2c.598C>T/c.340+770T>CVHL p.Arg200Trp/X1 p.Ser179Pro?2005/6 moM14.645Erythrocytosis—

      PatientID: II.2

      KindredID: 3

      Case: M, 0Y6M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: The patient had an affected brother (II.1) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

      CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

      CasePresentingHPOs: HP:0001901 (Polycythemia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R200W (c.598C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2232 https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

      CAID: N/A

      gnomAD: 0.0002016 https://gnomad.broadinstitute.org/variant/3-10191605-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: c.340+770T>C and R200W (c.598C>T)

      MultipleGeneVariants: Germline, VHL, c.340+770T>C

    1. variants of VHL in 18 probands

      PatientID: 14

      KindredID: 10

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family information provided.

      CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

      CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant, transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. A 15-year-old male with isolated left-sided hearing loss for more than 3 months was referred to the department of otorhinolaryngology with the suspected diagnosis of cholesteatoma. A computed tomography (CT) scan of the temporal bone, showing osseous destructions in the area of the jugular foramen but relatively little affection of the middle ear, had been performed prior to referral (Fig. 1). The patient had no vertigo, pain, or otorrhea, and the auditory canal and tympanic membrane appeared normal. For further evaluation, pure-tone audiometry showing a 40 to 75 dB conductive hearing loss over all frequencies, tympanometry showing a flat curve, and magnetic resonance imaging (MRI) of the temporal bone were performed. The first MRI images showed a lesion with polycyclic borders and osseo-destructive components in the left temporal bone.

      PatientID: None

      KindredID: 1

      Case: M, 15Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: None

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      CaseHPOFreeText: The patient had isolated left-sided hearing loss for more than 3 months. MRI showed a highly enhancing mass in the left temporal bone in the region of the jugular foramen, that measured 3.4 × 2.3 × 3.3 cm and exhibited a salt and pepper pattern in some areas. Definite histology confirmed ELST, and because a radical resection could not be guaranteed due to the highly infiltrative growth of the tumor, postoperative stereotactic radiation was initiated. The patient also had angiomatous lesions of the nasal and pharyngeal mucosa.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: The patient was screened for other VHL-associated tumors by fundoscopy and whole body positron-emission tomography-computed tomography, which did not show any pathological findings.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. In family E 12 patients suffer from the disease (Fig.1). Follow-up is 23 years. Another three patients haddied before the start ofthe screening program.

      KindredID: E

      GroupSize: 15

      DiseaseAssertion: VHL

      GroupNumberMales: 6

      GroupNumberFemales: 9

      GroupEthnicity: N/A

      GroupAgeRange: 27-55

      GroupInfo: In family E, 12 patients were diagnosed with VHL disease, and 3 patients passed away before this family was screened. The missense mutation p.V170D was found in this family. It is not specified in this paper which family members were genotyped and found to have this mutation.

      GroupPresentingHPOs: HP:0006880; HP:0000543, HP:0002666; HP:0001737; HP:0011732; HP:0000238; HP:0000648; HP:0005584; HP:0010797; HP:0003002; HP:0009711; HP:0002350; HP:0001407 (Cerebellar hemangioblastoma, Optic disc pallor, Pheochromocytoma, Pancreatic cysts, Abnormality of adrenal morphology, Hydrocephalus, Optic atrophy, Renal cell carcinoma, Hemangioblastoma, Breast carcinoma, Retinal capillary hemangioma, Cerebellar cyst, Hepatic cysts)

      GroupHPOFreeText: Overall, family E suffers from VHL clinical type 2B. Phenotypic information for each family member is described in detail in the paper (pages 557-558.) Briefly, Patient I-1 died of of renal cell carcinoma at age 55Y. Patients II-2 and II-4 died of obstructive hydrocephalus caused by a cerebellar haemangioblastoma at the ages of 33 and 39 years respectively. The proband (patient II-7), presented with obstructive hydrocephalus caused by a cerebellar hemangioblastoma, a secondary optic atrophy, no retinal angiomas at age 55. He also has pancreatic and adrenal cysts. His elder brother (patient II-3) has a small angioma on one optic disc, bilateral renal carcinomas, and cysts in cerebellum, adrenals and pancreas. His elder sister (patient II-5) has pale optic discs, an intra-medullary hemangioblastoma, unilateral renal carcinoma, bilateral phaeochromocytomas and a unilateral mamma carcinoma. Patient III-4, has a small parapapillary angioma and an ora serrata angioma with a dilated feeder artery and draining vein present in one eye. He also has cerebellar haemangioblastomas, bilateral phaeochromocytomas, renal carcinomas, pancreatic cysts, liver cysts and medullary haemangioblastomas. Patient III-6 has pale optic discs and suffers from a small cerebellar haemangioblastoma. Patient III-7 had bilateral phaeochromocytomas. Patient III-8 developed a very small angiomain one eye at the age of 28 years. She also has bilateral renal carcinomas. Patient III-10 has retinal angiomas in both eyes and also suffers from bilateral renal carcinomas and medullary haemangioblastomas. Patient III-11 suffers from a uni-lateral renal carcinoma. Patient III-12 has optic atrophy secondary to obstructive hydrocephalus because of a cerebellar haemangioblastoma and a macular retinal angioma that detached from the retina but is still attached to the optic disc. At age 27 new angiomas started to develop in both retinas including a recurrent angioma in the left macula with exudation in the posterior pole .She also suffered from a haemangioblastoma of the medulla oblongata and bilateral renal carcinomas. Patient III-13 developed retinal angiomas in one eye at the age of 32 years. Family member III-14 has pale optic discs with a normal neurological examination.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V170D (c.509T>A) Note: the cDNA change is not explicitly reported in this paper and was extrapolated from the reported protein coding change.

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/?new_evidence=true

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. 563T→C Ts Exon 3 188 CTG L L188P

      GroupID: 51

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

      Variant: p.L188P (c.563T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L188P (c.563T>C)

      MultipleGeneVariants: N/A

    2. 473T→C Ts Exon 3 158 CTG L L158P

      GroupID: 42

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A - only 1 patient reported here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: Other manifestations are possibly but not clearly reported

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

      Variant: p.L158P (c.473T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L158P (c.473T>C)

      MultipleGeneVariants: N/A

    3. 417–418delTC Fs Exon 2 139 TCT S Stop142

      GroupID: 33

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: N/A

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

      Variant: p.L140Qfs*3 (c.417_418delTC)

      CaseProblemVariantFreeText: recorded in paper as c.417_418delTC, this automaps to NM_000551.3:c.419_420delTC

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA357039 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.417_418delTC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift

      CivicName: L140fs (c.417_418delTC)

      MultipleGeneVariants: N/A

    1.  Sister 12c.349T > G, p.Trp117Gly–––53––

      PatientID: None

      KindredID: 6

      Case: F, 53Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Positive. The patient's sibling was the proband and had the mutation c.349T>G presenting with renal cell carcinoma, retinal angioma, hemangioblastoma, abnormality of the pancreas, and epididymal or ovarian cystadenoma.The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's third nephew were confirmed to have this genetic mutation. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

      CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

      CaseHPOFreeText: The patient presented with abnormality of the pancreas at age 53.

      CaseNotHPOs: HP:0002666, HP:0005584, HP:0009711, HP:0010797 (pheochromocytoma, renal cell carcinoma, retinal capillary hemangioma, hemangioblastoma)

      CaseNotHPOFreeText: The patient did not have a cystadenoma of the ovary.

      CasePreviousTesting: N/A

      PreviouslyPublished: 29330336

      Variant: p.W117G (c.349T>G)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:W117G (c.349T>G)

      MultipleGeneVariants: N/A

    2. Family 6+2c.349T > G, p.Trp117GlyYes136444440–44

      PatientID: None

      KindredID: 6

      Case: Sex Unknown, 44Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Positive. Patient's son who was confirmed to have this mutation presented with hemangioblastoma at age 12. The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's first sister and third nephew were confirmed to have this genetic mutation. The first sister presented with abnormality of the pancreas at age 53. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

      CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0009711 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)

      CaseHPOFreeText: The patient presented with hemangioblastoma at age 36. At age 40 he/she presented with pancreatic cysts or tumours. At age 44 the patient had retinal angioma, renal cell carcinoma, and epididymal or ovarian cystadenoma.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29330336

      Variant: p.W117G (c.349T>G)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:W117G (c.349T>G)

      MultipleGeneVariants: N/A

    3. Family 4−1c.275insCCdelAYes123––24––

      PatientID: None

      KindredID: 4

      Case: Unknown, 24Y0M, Chinese

      DiseaseAssertion:VHL

      FamilyInfo: None.

      CasePresentingHPOs: HP:0010797, HP:0001732 (hemangioblastoma, abnormality of the pancreas)

      CaseHPOFreeText:The patient presented with hemangioblastoma at age 23. One year later he/she was found to have pancreatic cysts or tumors.

      CaseNotHPOs: HP:0009711, HP:0002666, HP:0005584 (retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma)

      CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

      CasePreviousTesting: N/A

      PreviouslyPublished: 29330336

      Variant: p.D92Afs*40(c.275delAinsCC)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA1139768933 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275delAinsCC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: delins

      CivicName:D92fs(c.275delAinsCC)

      MultipleGeneVariants: N/A

    1. PatientID: 30

      KindredID: 30

      Case: F, 27Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: No family history of VHL.

      CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

      CasePresentingHPOs: HP:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

      CaseHPOFreeText: CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

      CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19270817

      SupplementalData: N/A

      Variant: p.L128P (c.383T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 1208816, https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L128P (c.383T>C)

      MultipleGeneVariants: N/A

    2. PatientID: 38

      KindredID: 38

      Case: M, 22Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: Family positive for VHL. No further details provided.

      CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

      CasePresentingHPOs: HP:0009711; HP:0010797 (Retinal capillary hemangioma, Hemangioblastoma)

      CaseHPOFreeText: Multiple or bilateral retinal hemangioblastomas. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

      CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19270817

      SupplementalData: N/A

      Variant: p.R161* (c.481C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition; stop_gained

      CivicName: R161* (c.481C>T)

      MultipleGeneVariants: N/A

    1. Of the 13 individuals tested, V:2, IV:4, IV:6, III:2, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. With the exception of family member IV:2, none of these individuals reported any features characteristic of VHL disease.

      PatientID: IV:6

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: The patient had two siblings both of whom carried the P25L mutation. One was asymptomatic (IV:4) whereas another (IV:2) presented with retinal hemangioma and renal cysts. Her cousin (IV:7) was diagnosed at the age of 47 years with renal cell carcinoma and subsequently died at the age of 48 years. Her great grandmother (I:2) had died of a brain tumor in her late 50s. Her grandfather (II:3) had a brain tumor at the age of 53 years and died aged 78 years. As well, her grandfather's sister (II,1) reportedly died of stomach cancer in her 80s. Of the 13 family members tested, V:2, IV:4, IV:6, III:2, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P25L (c.74C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

      CAID: N/A

      gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName:P25L (c.74C>T)

      MultipleGeneVariants: N/A

    2. . Of the 13 individuals tested, V:2, IV:4, IV:6, III:2, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. With the exception of family member IV:2, none of these individuals reported any features characteristic of VHL disease.

      PatientID: III:11

      KindredID: 1

      Case: F, 75, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:2 and III:3). The patient's sister (III:2) had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her niece, (IV:2) had three children and one was found to carry the mutation. The patient's brother (III:3) had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation (IV:7). The patient had three unaffected children who did not carry the mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Ongoing clinical follow up of the individuals with P25L over a period of 5 years has continued to show no evidence of additional clinical involvement of VHL disease.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P25L (c.74C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

      CAID: N/A

      gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName:P25L (c.74C>T)

      MultipleGeneVariants: N/A

    1. 18M/34ASB/L PCCVHL3c.482G>Ap.(Arg161Gln)Substitution (missense)Disease causing

      PatientID: 18

      KindredID: 18

      Case: M, 34Y0M, Asian Indian

      DiseaseAssertion: pheochromocytoma

      FamilyInfo:  None - Apparently sporadic

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: bilateral pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    2. 21F/35ASUnilateral PCCVHL3c.548C>G (Novel)p.(Ser183Trp)Substitution (missense)Disease causing

      PatientID: 21

      KindredID: 21

      Case: F, 35Y0M, Asian Indian

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: None - apparently sporadic

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: unilateral pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S183W (c.548C>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 219158 https://www.ncbi.nlm.nih.gov/clinvar/variation/219158/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: S183W (c.548C>G)

      MultipleGeneVariants: N/A

    3. 27F/26FSB/L PCC+sPGLPNETVHL3c.499C>Tp.(Arg167Trp)Substitution (missense)Disease causing

      PatientID: 27

      KindredID: 27

      Case: F, 26Y0M, Asian Indian

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Positive family history

      CasePresentingHPOs: HP:0002666; HP:0002668; HP:0030405 (pheochromocytoma; paraganglioma; pancreatic endocrine tumor)

      CaseHPOFreeText: patient had bilateral pheochromocytoma and sympathetic paraganglioma; and PNETs

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 4

      KindredID: 4

      Case: Sex Unknown, 26Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0000107; HP:0009711; HP:0002666; HP:0010797 (Renal cyst, Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma)

      CaseHPOFreeText: CNS hemangioblastoma, pheochromocytoma, renal cystic lesion and retinal hemangioblastoma.

      CaseNotHPOs: HP:0006770; HP:0001732 (Clear cell renal cell carcinoma, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.S80I (c.239G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S80I (c.239G>T)

      MultipleGeneVariants: N/A

    2. PatientID: 160

      KindredID: 160

      Case: Sex Unknown, 14Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711; HP:0002666; HP:0000107; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

      CaseHPOFreeText: Retinal hemangioblastoma, pheochromocytoma, renal cystic lesion and pancreatic cyst or tumor.

      CaseNotHPOs: HP:0006770; HP:0010797 (Clear cell renal cell carcinoma, Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.L178P (c.533T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant noted as c.533C>T/p.L178P which was assumed to be c.533T>C.

      MutationType: missense_variant;transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    3. PatientID: 105

      KindredID: 105

      Case: Sex Unknown, 33Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history noted but no details provided.

      CasePresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0001732 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

      CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, renal cystic lesion and retinal hemangioblastoma.

      CaseNotHPOs: HP:0006770; HP:0002666 (Clear cell renal cell carcinoma, Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.P86A (c.256C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: P86A (c.256C>G)

      MultipleGeneVariants: N/A

    4. PatientID: 110

      KindredID: 110

      Case: Sex Unknown, 59Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history noted but no details provided.

      CasePresentingHPOs: HP:0001732; HP:0002666 (Abnormality of the pancreas, Pheochromocytoma)

      CaseHPOFreeText: Pancreatic cyst or tumor and pheochromocytoma.

      CaseNotHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0006770 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Clear cell renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.P86A (c.256C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: P86A (c.256C>G)

      MultipleGeneVariants: N/A

    5. 117 31 c.465_470del6 p.156_157delYT x x x De novo Parents and siblings -

      PatientID: 117

      KindredID: 117

      Case: Sex Unknown, 31Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Parents and siblings were all negative for the mutation. No phenotype details are noted for these family members.

      CasePresentingHPOs: HP:0010797; HP:0001732; HP:0009711 (Hemangioblastoma, Abnormality of the pancreas, Retinal capillary hemangioma)

      CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pancreatic cyst or tumor.

      CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.Y156_T157del (c.465_470del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA16621939, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.465_470del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion; deletion

      CivicName: Y156_T157del (c.465_470del)

      MultipleGeneVariants: N/A

    6. PatientID: 89

      KindredID: 89

      Case: Sex Unknown, 49Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Positive VHL family history.

      CasePresentingHPOs: HP:0009711, HP:0006770 (retinal capillary hemangioma, clear cell renal cell carcinoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797, HP:0001737, HP:0002666, HP:0000107 ( hemangioblastoma, pancreatic cyst, pheochromocytoma, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2, S3.

      Variant: p.P86L(c.257C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: CA020186 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86L(c.257C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 4

      KindredID: Unknown

      Case: M, 31Y0M, Dutch

      DiseaseAssertion: VHL

      FamilyInfo: Unknown - study sampled 15 patients from 5 families

      CasePresentingHPOs: HP:0006880; HP:0000107 (cerebellar hemangioblastoma, renal cyst)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseNotHPOFreeText: No evidence of left or right eye angiomas

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V170D (c.509T>A)

      LegacyVariant: p.V241D

      CaseProblemVariantFreeText: Variant determined through the assumption of the authors using Latif et al 1993 (AF010238.1) transcript and adding 71bp to the protein sequence.

      ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. c.565delG1 (1%)130HBc, Cr

      PatientID: None

      KindredID: 16

      Case: Sex Unknown, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

      CasePresentingHPOs: HP:0006880; HP:0000107 (Cerebellar hemangioblastoma, Renal cyst)

      CaseHPOFreeText: VHL Type 1.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

      Variant: p.E189Kfs*13 (c.565del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625267, https://www.ncbi.nlm.nih.gov/clinvar/variation/625267/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant; deletion

      CivicName: E189fs (c.565del)

      MultipleGeneVariants: N/A

    2. c.509T > A15 (20%)2a/b45 (16–71)HBr, HBc,HBsc, RCC, pNET, Pheo, Cr, Cp

      atientID: None

      KindredID: 15

      Case: Sex Unknown, 71Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

      CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0001737; HP:0002666 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pancreatic cysts, Pheochromocytoma)

      CaseHPOFreeText: VHL Type 2a/b.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

      Variant: p.V170D (c.509T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. 10Cerebellum479 T/CL89PMissenseNINegative

      PatientID: 10

      KindredID: 4

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Patient 10 and 4 are related with the same p.L89P mutation and cerebellar hemangioblastomas. Their exact relation was not clear.

      CohortInfo: A total of 42 CNS haemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient presented with a VHL-related tumor in the cerebellum.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L89P (c.266T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L89P (c.479T>C)

      ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    2. 3aCerebellum699 C/GC162WMissenseNegativeNegative3bCerebellum699 C/GC162WMissenseLOHNegative

      PatientID: 3 (tumour samples 3a, 3b)

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: A total of 42 CNS haemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient presented with 2 VHL-related tumors in the cerebellum (a,b). Tumor b presented with LOH positive somatic information but negative methylation.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.C162W (c.486C>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.C162W (c.699C>G)

      ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: C162W (c.486C>G)

      MultipleGeneVariants: N/A

      
      
    1. GroupID: 16

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E160Sfs*10 (c.477del)

      LegacyVariant: c.688delA

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182959, https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant reported as c.688delA which was mapped to c.477del.

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: E160fs (c.477del)

      MultipleGeneVariants: N/A

    1. family B, with pheochromocytoma only phenotype, we detected a previously not described c.463G>A/p.Val84Met replacement. Within this family, a prenatal diagnosis was also performed.

      PatientID: BII2

      KindredID: B

      Case: M, 40Y0M, Serbian

      DiseaseAssertion: VHL

      FamilyInfo: Families were selected based on their clinical data and family history. Patient’s father (BI1) had pheochromocytoma, but was not genetically tested. The patient’s son (BIII3) developed pheochromocytoma at the age of one, but progressed to bilateral pheochromocytoma 3 years later. Genetic testing revealed the same mutation in the patient and his son. In fact, a sample of amniotic fluid was taken from the patient’s wife (BII2) during the 16th week of pregnancy for prenatal testing, which was later confirmed to be the same point mutation as BII2. See pedigree in figure 1.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: The first symptoms of pheochromocytoma appeared in the patient at age 40Y0M.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V84M (c.250G>A)

      LegacyVariant: p.V84M (c.463G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428813, https://www.ncbi.nlm.nih.gov/clinvar/variation/428813/

      CAID: N/A

      gnomAD: 0.000004376, https://gnomad.broadinstitute.org/variant/3-10183781-G-A

      VariantEvidence: N/A

      MutationType: missense variant; transition

      CivicName: V84M (c.250G>A)

      MultipleGeneVariants: N/A

    1. PatientID: 5

      KindredID: 2

      Case: F, 20Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: Another member of this family (Gen 1) presented with the same mutation, bilateral pheochromocytoma, RCC as well as neural hemangioblastoma that ultimately caused his death.

      CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Bilateral pheochromocytoma.

      CaseNotHPOs: HP:0005584; HP:0001737; HP:0009711; HP:0010797; HP:0002668; HP:0030405 (Renal cell carcinoma, Pancreatic cysts, Retinal capillary hemangioma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    2. PatientID: 11

      KindredID: 4

      Case: M, 27Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: 2 other family members (relation unclear) presented with the same variant. Patient 9 (Gen 2) of these presented with unilateral pheochromocytoma and PNET. Patient 10 (Gen 1) presented with bilateral pheochromocytoma and sympathetic paraganglioma and PNET.

      CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

      CasePresentingHPOs: HP:0002666; HP:0002668; HP:0030405; HP:0009711; HP:0010797 (Pheochromocytoma, Paraganglioma, Pancreatic endocrine tumor, Retinal capillary hemangioma, Hemangioblastoma)

      CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Metastasis found at age 27. Age of onset for pheochromocytoma and paragangliomas is stated as 12Y and 15Y but it is not clear which age pertains to which phenotype.

      CaseNotHPOs: HP:0001737; HP:0005584 (Pancreatic cysts, Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y98S (c.293A>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 219160, https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: Y98S (c.293A>C)

      MultipleGeneVariants: N/A

    1. This mutation was inherited from the paternal allele

      PatientID: None (father)

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: No significant family history.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V194G (c.581T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428810, https://www.ncbi.nlm.nih.gov/clinvar/variation/428810/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: In silico analysis was performed using the PolyPhen-2 program and SIFT analysis. In the PolyPhen-2 analysis, the prediction score was 1.000, which indicated “probably damaging.” In addition, SIFT analysis of V194G indicated a SIFT score of 0, which indicates a seriously damaging mutation.

      MutationType: missense_variant;transversion

      CivicName: V194G (c.581T>G)

      MultipleGeneVariants: N/A

    1. PatientID: N/A

      KindredID: 23530

      Case: Age unknown, Sex unknown, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Paper states familial VHL

      CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0000107 (hemangioblastoma; renal cell carcinoma; pacreatic cysts; renal cyst)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes (Specifically Supp. Table S2)

      Variant: p.L89P (c.266T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    1. 7M–1c.233A > Gp.Asn78Ser11414––14, M14, B4

      PatientID: 7

      KindredID: 7

      Case: M, 14Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: None

      CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

      CasePresentingHPOs: HP:0010797, HP:0000107, HP:0009711, HP:0001737(hemangioblastoma, renal cyst, retinal capillary hemangioma, pancreatic cysts)

      CaseHPOFreeText: The patient was found to have a CNS hemangioblastoma, retinal capillary hemangioma, multiple pancreatic cysts and bilateral renal cysts at age 14. MRI of the brain showed a tiny well-enhanced nodule at the cervicomedullary junction with an adjacent prominent vascular structure.

      CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    2. 10F–3c.500G > Ap.Arg167Gln159–––59, M59, B4

      PatientID: 10

      KindredID: 10

      Case: F, 59Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: None

      CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

      CasePresentingHPOs: HP:0010797, HP:0030405, HP:0000107(hemangioblastoma, pancreatic endocrine tumour, renal cyst)

      CaseHPOFreeText: This patient underwent abdominal CT; multiple renal cysts, a hypervascular mass in the pancreatic body, and a cystic mass in the pancreatic head and tail were found. Pylorus preserving pancreaticoduodenectomy was performed in this patient. Two months after surgery, gait disturbance appeared. MRI of the brain revealed multiple enhancing masses in both cerebellums, which were pathologically found to be hemangioblastoma.

      CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666 (retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167Q (c.500G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

      CAID: N/A

      gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500 G >A)

      MultipleGeneVariants: N/A

    1. 2 (100)

      GroupID: 37

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: These 2 patients with a c.463G>C mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V155L (c.463G>C)

      LegacyVariant: N/A

      GroupProblemVariantFreeText: N/A

      ClinVarID: 1023631 https://www.ncbi.nlm.nih.gov/clinvar/variation/1023631

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V155L (c.463G>C)

      MultipleGeneVariants: N/A

    2. 2 (50)

      GroupID: 24a

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: These 2/4 patients with a P86H (c.257C>A) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86H (c.257C>A)

      LegacyVariant: N/A

      GroupProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351750632 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C>A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: P86H (c.257C>A)

      MultipleGeneVariants: N/A

    3. 1 (50)

      GroupID: 19a

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes - Supplementary Table S1

      Variant: p.R79G (c.235C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: R79G (c.235C>G)

      MultipleGeneVariants: N/A

    4. 1 (50)

      GroupID: 35a

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes - Supplementary Table S1

      Variant: p.F136S (c.407T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

      CAID: N/A

      gnomAD: 0.000003976 https//gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: F136S (c.407T>C)

      MultipleGeneVariants: N/A

    5. 1 (100)

      GroupID: 18

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes - Supplementary Table S1

      Variant: p.N78S (c.233A>G)

      LegacyVariant: N/A

      GroupProblemVariantFreeText: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    6. 1 (50)

      GroupID: 19b

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual did NOT have retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

      CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes - Supplementary Table S1

      Variant: p.R79G (c.235C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: R79G (c.235C>G)

      MultipleGeneVariants: N/A

    1. 4 16.1 Retinal angioma, cervical spine hemangioblastoma, cysts of pancreas and kidney No Germline G to A base change at −1 position of splice acceptor sequence for exon 2

      PatientID: 4

      KindredID: 4

      Case: 16Y1M, sex unknown ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: None

      CasePresentingHPOs: HP:0006880; HP:0009711; HP:0009713; HP:0001737; HP:0000107 (cerebellar hemangioblastoma; retinal capillary hemangioma; spinal hemangioblastoma; pancreatic cysts; renal cyst)

      CaseHPOFreeText: spinal hemangioma was cervical.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.341-1G>A

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 823743 https://www.ncbi.nlm.nih.gov/clinvar/variation/823743/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Germline G to A base change at 1 position of splice acceptor sequence for exon 2

      MutationType: splice_site_variant

      CivicName: Splice Site (c.341-1G>A)

      MultipleGeneVariants: N/A

    1. A 32-year old man was invited to our centre for a consultation at the Polish VHL Registry as a member of a family with suspected von Hippel-Lindau disease (VHL). He had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone. The patient was operated on a few months later and a histopathological diagnosis of choroid plexus papilloma was made. Two years later he was reoperated on due to recurrence and treated with adjunctive radiotherapy. Three years later the patient developed ataxia and was treated surgically because of a cerebellar tumour that was histopathologically diagnosed as haemangioblastoma. Due to recurrence of this tumour the patient was reoperated on two years later. He also had a history of retinal capillary angioma treated by cryo- and laser therapy.

      PatientID: None

      KindredID: 1

      Case: M, 32Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Many of the patient’s family members developed lesions in sites suggesting VHL including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and some of the family members have lost their sight because of retinal detachment (probably in the case of retinal haemangiomas). However, the diagnosis of VHL has not been established in the family. Two of his children were also found to have the NM_000551.3:c.194C>T(S65L) mutation after analysis of blood samples.

      CasePresentingHPOs: HP:0030393; HP:0010797; HP:0009711 (Endolymphatic sac tumour, hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: The patient had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone with a recurrence two years later (at 21Y). The patient was originally histopathologically diagnosed with choroid plexus papilloma, but was re-diagnosed with an endolymphatic sac tumour on reexamination of the sample. Three years later (24Y) the patient developed ataxia because of a cerebellar tumour that was histopathologically diagnosed as hemangioblastoma. He had a recurrence two years later (26Y). He also had a history of retinal capillary angioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: p.S65L (c.407C>T)

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      gnomAD: 0.000, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 1

      KindredID: 1

      Case: M, 68Y0M, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: None.

      CasePresentingHPOs: HP:0002666; HP:0009711; HP:0000107 (pheochromocytoma, retinal capillary hemangioma, renal cyst)

      CaseHPOFreeText: Patient was found observed to have retinal angioma (retinal capillary hemangioma) and a right kidney cortex cyst (30mm). Patient's pheochromocytoma was found incidentally and he remained asymptomatic with steady weight.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET, SDHB, SDHC and SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P25L (c.74C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

      CAID: N/A

      gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P25L (c.74C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 6

      KindredID: 6

      Case: F, 29Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 55 patients treated at Asan Medical Center in Korea treated between January 1995 and February 2013 clinically diagnosed with VHL disease and presenting with pancreatic lesions.

      CasePresentingHPOs: HP:0001737, HP:0030405 (pancreatic cysts, pancreatic endocrine tumor)

      CaseHPOFreeText: The patient presented with serous cystadenoma and pancreatic endocrine tumour at age 26. She was followed up 35.8 months later when her disease was reported to have progressed.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86S (c.256C>T)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 178692 https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    1. VHL_3Frozenc.482G>Ap.Arg161GlnM37AdrenalPCCB

      PatientID: VHL_3 (tumor ID)

      KindredID: 3

      Case: M, 37Y0M, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 37Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. No abstract available

      PatientID: V-1

      KindredID: 1

      Case: M, 46Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: The patient’s grandmother and two uncles had died with cerebellar hemangioblastoma, although genetic testing was not performed. The patient’s father presented with cerebellar hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and serous cystadenoma at 68Y, adrenal pheochromocytoma at 73Y, and clear cell renal cell carcinoma metastasis in the thyroid at 74Y; he was found to carry the same mutation the patient carried. One of the patient’s sons, a 10Y male, was also found to carry the same mutation as the patient but was asymptomatic. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

      CasePresentingHPOs: HP:0009726; HP:0000107; HP:0001737 (Renal tumour, renal cyst, pancreatic cyst)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R82P(c.245G>C)

      LegacyVariant: N/A

      ClinVarID: 193118, http://www.ncbi.nlm.nih.gov/clinvar/variation/193118

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R82P(c.245G>C)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 8

      Case: M, 8Y0M, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: His father had the same VHL mutation and presented with hemangioblastoma, clear cell renal cell carcinoma, and abnormality of the pancreas.

      CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0010797, HP:0006770, HP:0001732 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, hemangioblastoma, clear cell renal cell carcinoma, abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W88* (c.263G>A)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName:W88*(c.263G>A)

      MultipleGeneVariants: N/A

    1. missense mutations

      PatientID: None

      KindredID: 77

      Case: Age, sex ethnicity unknown

      DiseaseAssertion: unknown; paper focused only on pheochromocytoma

      FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 77

      CasePresentingHPOs: Unknown

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V170D (c.509T>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.V170D (c.722T>A)

      ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. 2bF““““PPGL, HBA CNS/Ret, RCC, PanNET

      PatientID: 2b

      KindredID: 2

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: An unspecified relative (proband - 2a) had the same mutation with renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, pancreatic cysts and pancreatic endocrine tumors.

      CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0002668; HP:0030405 (renal cell carcinoma; hemangioblastoma; retinal capillary hemangioma; pancreatic cyst; pancreatic endocrine tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: MEN1/ RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N78S (c.233A>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    2. 8PExon 1Missensec.340G>Cp. Gly114ArgHBA Ret, PanNET

      PatientID: 8

      KindredID: 6

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711; HP:0030405 (Retinal capillary hemangioma; pancreatic endocrine tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: MEN1/ RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193 https://www.ncbi.nlm.nih.gov/clinvar/variation/223193

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: G114R (c.340G>C)

      MultipleGeneVariants: N/A

    1. detected point germline vhl mutations in 14 patients

      PatientID: 17

      KindredID: 17

      Case: 20Y0M, sex unknown, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioma)

      CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. GroupID: 39

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711(retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797, HP:0002666, HP:0005584 (hemangioblastoma, pheochromocytoma, renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P86L(c.257C>T)

      LegacyVariant: p.P157L (c.470C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86L(c.257C>T)

      MultipleGeneVariants: N/A

    1. PMID: 7977367

      PatientID: N/A

      KindredID: A-704 (cell line)

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Renal cell carcinoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

      CaseHPOFreeText: Described as sporadic RCC from cell line A-704

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.I180N (c.539T>A)

      LegacyVariant: p.I251N (c.752T>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756277 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.539T%3EA

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: missense_variant; transversion

      CivicName: I180N (c.539T>A)

      MultipleGeneVariants: N/A

    2. PMID: 7977367

      KindredID: 21

      DiseaseAssertion: VHL

      GroupSize: Unknown

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This is a family belonging to prefigure No. 21. They are described as ‘VHL-affected’.

      GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

      GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D121G (c.362A>G)

      LegacyVariant: p.D192G (c.575A>G)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223200 https://www.ncbi.nlm.nih.gov/clinvar/variation/223200/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: D121G (c.362A>G)

      MultipleGeneVariants: N/A

    1. germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany.

      GroupID/ KindredID: VHL 2

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      FamilyInfo: 3 affected members belong to this VHL type 2A family. One representative affected member was analyzed with this mutation, and VHL was diagnosed clinically in this index person. It is unclear as to whether the additional patients had this precise mutation, although assumed.

      GroupPresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

      GroupHPOFreeText: all 3 individuals had Pheos, whereas only 1 person had a retinal capillary hemangioma.

      GroupNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

      GroupNotHPOFreeText: No patients had the above tumors

      GroupPreviousTesting: N/A

      PreviouslyPublished: 11134110, 9681856, 11850829

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: p.Y98H (c.505T>C)

      CaseProblemVariantFreeText: N/A

      ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    2. germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany.

      GroupID/ KindredID: VHL 27

      Case: Age unknown, Sex Unknown, German

      DiseaseAssertion: VHL

      FamilyInfo: None - diagnosis of VHL was clinically confirmed in the individual however a VHL type could not be determined due to the small size of the pedigree

      CasePresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584; HP:0001737; HP:0009715; HP:0002666 (renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis, pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 11134110, 9681856, 11850829

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: p.Y98H (c.505T>C)

      CaseProblemVariantFreeText: N/A

      ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. PatientID: V-10

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

      CaseNotHPOs: HP:0005584; HP:0009711 (Renal cell carcinoma, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    2. PatientID: III-10

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

      CaseNotHPOs: HP:0005584; HP:0009711 (Renal cell carcinoma, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    3. PatientID: IV-15

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

      CaseNotHPOs: HP:0005584; HP:0009711 (Renal cell carcinoma, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    1. PatientID: 1

      KindredID: 95

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: one pheochromocytoma was detected in this patient

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R167W (c.712C>T)

      ClinVarID: 2218 (https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/)

      CAID: N/A

      gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

      VariantEvidence: LOH detected

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 138 (Second cousin)

      KindredID: 18

      Case: M, 49Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

      CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

      CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis of retinal angioma is unknown.

      CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0010797 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

      SupplementalData: Supplementary Table 1.

      Variant: p.R167W (c.499C>T)

      LegacyVariant: c.712C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. 7 F/40 PCC VHL 3 c.499C>T (p.Arg167Trp) Pre-NGS Sanger Rt adrenal 4.6 Benign No Hemangioblastoma of brainstem, pancreatic NET, RCC Incidental Noradrenergic

      PatientID: 7

      KindredID: 7

      Case: F, 40Y0M, Korean

      DiseaseAssertion: Assumed VHL

      FamilyInfo: No information provided.

      CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405; HP:0006880 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma)

      CaseHPOFreeText: The patient presented with adrenal pheochromocytoma. She also had other tumours, including renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma (see table 3).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET, NF1, MAX, SDHA/SDHAF2/SDHB/SDHC/SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. An 11-year-old female was admitted with complaints of episodes of headache, sweating, palpitation along with history of vomiting, and blurring vision; and examination revealed tachycardia, hypertension (230/130 mmHg). Subsequent evaluation revealed elevated NMN (2959 μg/ml). CECT revealed a right adrenal mass 3 × 3 cm and hence she was provisionally diagnosed as a case of right PCC with probability of MEN 2A or VHL in view of young age. However, there was no family history and no evidence of medullary thyroid cancer or HPT in her or her siblings. She underwent laparoscopic right adrenalectomy after adequate alpha blockade. HPE confirmed PCC without hyperplasia of normal adrenal tissue. She was subsequently followed up. She then presented 6 years later with history of paroxysms and one episode of hypertension. On examination her blood pressure was found to be 180/110 on standing and 150/110 on lying down. Her UNMN was 6,620 μg/ml at 24 h (0–600). PET CT revealed a 5.8 × 5.5 cm left adrenal PCC. She was then put on alpha blockade and underwent a left laparoscopic adrenalectomy under steroid cover. Postop period was uneventful and HPE revealed PCC without adrenal hyperplasia. Her postoperative UMN returned to normal levels. She was discharged on and is doing well in follow-up. It was also found that her cousin had undergone bilateral adrenalectomy with us (case 2) during her period of follow-up and he was found to be having a positive VHL gene mutation; hence she was also tested for VHL mutation and was found to be harboring VHL gene mutation also. ({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3 [VHL]:c.382C>Tin exon 2. Protein change: leucine to phenylalanine).

      PatientID: 1

      KindredID: 1

      Case: F, 11Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Her cousin (case 2) underwent a bilateral adrenalectomy and had the same VHL mutation.

      CasePresentingHPOs: HP:0006748, HP:0002865 (Adrenal pheochromocytoma, Medullary thyroid carcinoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584, HP:0010797 (renal cell carcinoma, hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L128F (c.382C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496060 https://www.ncbi.nlm.nih.gov/clinvar/variation/496060/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L128F (c.382C>T)

      MultipleGeneVariants: N/A

    1. All family members underwent clinical, laboratory, imaging, and genetic evaluation.

      PatientID: V-9

      KindredID: 1

      Case: M, Age Unknown, Iranian

      DiseaseAssertion: asymptomatic

      FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0000077 (abnormality of the kidney)

      CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167Q (c.500G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

      CAID: N/A

      gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. F60yellowFemale60Trp117Cys3rd R (prior L radical)Never24.76No

      PatientID: None

      KindredID: 4

      Case: F, 60Y0M, Ethnicity Unknown

      DiseaseAssertion: Clear Cell Renal Cell Carcinoma

      FamilyInfo: N/A

      CohortInfo: The National Cancer Institute has a frozen tumour bank of ccRCC tumours that have been removed from VHL patients. We selected six patients, three males and three females, with at least five tumours from a single surgery from one kidney.

      CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

      CaseHPOFreeText: The patient presented with ccRCC at age 60.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W117C(c.351G>X)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: This protein change corresponds to both c.351G>C or c.351G>T.

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:W117C(c.351G>X)

      MultipleGeneVariants: N/A

    1. Patient 3c.500G>A, p.(Arg167Gln)missense3

      PatientID: 3

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

      CaseHPOFreeText: Hereditary PNET with a confirmed germline mutation.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167Q (c.500G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

      CAID: N/A

      gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. 16 different families

      PatientID: 4

      KindredID: 5

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G93R (c.277G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant, transversion

      CivicName: G93R (c.277G>C)

      MultipleGeneVariants: N/A

    1. PatientID: 8

      KindredID: 8

      Case: F, 56Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history but no further details were provided. CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Diagnosed with VHL type 2A. Bilateral pheochromocytoma at 31Y. Metastasis in liver, lung and skull bones, 25 years after initial diagnosis. Last follow-up 25 years after diagnosis. Patient died but the age of death is not specified.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

      SupplementalData: N/A

      Variant: p.R161Q (c.482G>A)

      LegacyVariant: c.695G>A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Authors report variant as “695, G to A”. Assumed to be reported in legacy nomenclature (AF010238.1 (Latif et al.)) and mapped to c.482G>A (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. F 18 VHL 2 B/L PCC, PNET c. IVS2+3A>G ?splice site

      PatientID: None

      KindredID: 3

      Case: F, 18Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666; HP:0030405 (pheochromocytoma; pancreatic endocrine tumor)

      CaseHPOFreeText: patient had a bilateral pheochromocytoma and PNETs

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ SDHC

      PreviouslyPublished: 23397066

      SupplementalData: N/A

      Variant: c.463+3A>G

      LegacyVariant: c.IVS2+3A>G

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428796 https://www.ncbi.nlm.nih.gov/clinvar/variation/428796/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Region (c.463+3A>G)

      MultipleGeneVariants: N/A

    1. The proband (III-4) was a 28-year-old male who consulted because of a history of VHL disease in his family. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumours, whereas his grandfather (I-2) had unspecified abdominal tumours. All these relatives died in their early 30s (Table 1). Magnetic resonance (MR) imaging of brain and spine was performed in this subject demonstrating cerebellar HB. Ophthalmologic examination revealed VA of 6/6 in both eyes, and IOP of 14 mmHg in the right eye and of 18 mmHg in the left eye. No anomalies were found at biomicroscopic inspection; funduscopic evaluation of the right eye showed a well defined orange-red mass corresponding to a peripheral retinal HB of approximately 1 disc diameter associated with a prominent feeding artery and to a draining vein. FAG demonstrated hyperfluorescence of this retinal angioma as well as enlargement and tortuosity of retinal blood vessels.

      PatientID: III-4 (Proband)

      KindredID: 1

      Case: M, 28Y0M, Mexican

      DiseaseAssertion: VHL

      FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

      CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

      CasePresentingHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)

      CaseHPOFreeText: MRI of brain and spine was performed in this subject demonstrating cerebellar HB. Funduscopic evaluation of the right eye showed a well defined orange-red mass corresponding to a peripheral retinal HB of approximately 1 disc diameter associated with a prominent feeding artery and to a draining vein. FAG demonstrated hyperfluorescence of this retinal angioma as well as enlargement and tortuosity of retinal blood vessels.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Family pedigree (Figure 1(a))

      Variant: p.R82P (c.245G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R82P (c.245G>C)

      MultipleGeneVariants: N/A

    1. PatientID: V-3

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: Age of onset not provided. Deceased.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y112N (c.334T>A)

      LegacyVariant: T547A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

      MutationType: missense_variant;transversion

      CivicName: Y112N (c.334T>A)

      MultipleGeneVariants: N/A

    1. In family 2 (fig. 1), the affected daughter (IV:6) was diagnosed with VHL disease at age 15 years, when she developed symptoms caused by spinal cord hemangioblastomas (fig. 2C). At age 20 years, she was diagnosed with multiple cystic lesions in the right kidney, a solid lesion of the left kidney, multiple pancreatic cysts, and a small peripheral retinal angioma

      PatientID: IV-6

      KindredID: 2

      Case: F, 23Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Her 48Y father (Patient III-4) presented with hematuria at age 39Y and was found to have clear-cell renal-cell carcinoma, renal cysts, pancreatic cysts, and multiple hemangioblastomas of the cerebellum and lower brainstem. Her father was found to have mosaic VHL disease and the NM_000551.3:c.227_229del mutation the patient carried in approximately one of seven peripheral blood lymphocytes. The patient’s mother was unaffected. Of the patient’s three sisters and two brothers, one underwent clinical examination and two underwent genetic testing of unclear nature, and were found to be unaffected. The remaining two siblings were not evaluated.

      CasePresentingHPOs: HP:0009713; HP:0001737; HP:0000107; HP:0000077; HP:0009711 (Spinal hemangioblastoma, pancreatic cyst, renal cyst, renal lesion, retinal hemangioma)

      CaseHPOFreeText: The 23Y female patient was diagnosed with VHL disease at age 15 years, when she developed symptoms caused by spinal cord hemangioblastomas. At age 20 years, she was diagnosed with multiple cystic lesions in the right kidney, a solid lesion of the left kidney, multiple pancreatic cysts, and a small peripheral retinal angioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del(c.226_228delTTC)

      LegacyVariant: p.F76del(c.439_441delTTC)

      ClinVarID: N/A

      CAID: CA357012

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: F76del(c.226_228delTTC)

      MultipleGeneVariants: N/A

    1. PatientID: 21 (tumour 36)

      KindredID: 4

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Two other members of this patient's family (patient 19 and patient 20) were found to harbour the same VHL gene mutation.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: Patient had one benign pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: 7759077, 9681856

      SupplementalData: N/A

      Variant: p.L188V (c.562C>G)

      LegacyVariant: p.L188V (c.775C>G)

      CaseProblemVariantFreeText: N/A

      ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

      CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

      gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

      VariantEvidence: Refer to Table 1 for LOH information.

      MutationType: missense_variant;transversion

      CivicName: L188V (c.562C>G)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: S-FPH1

      Case: Sex Unknown, Age Unknown, Korean

      DiseaseAssertion: VHL

      FamilyInfo: 2 affected individuals in this family. Pheochromocytoma is noted as familial.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Family diagnosed with VHL type 2C.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V84L (c.250G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2236, https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V84L (c.250G>T)

      MultipleGeneVariants: N/A

    1. 22m2811n13.6n430 C/T+0.1

      PatientID: 22

      KindredID: 22

      Case: M, 28Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: No details on family information.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q73* (c.217C>T)

      LegacyVariant: c.430C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223164, https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Q73* (c.217C>T)

      MultipleGeneVariants: N/A

    1. In this paper we report the presence of a single nucleotide mutation in exon 3 of VHL gene c499 C>T causing substitution of Arginine by Tryptophan at position 167 (R 167 W).

      PatientID: 1 (III:1)

      KindredID: 1

      Case: F, 39Y0M, Persian

      DiseaseAssertion: VHL

      FamilyInfo: 4 sisters were treated with bilateral adrenal mass resection. Patient 2 died at 23Y and patient 3 died at 21Y due to complications associated with VHL. 2 years later, 3 of their other sisters were found to have the mutation. It is assumed that all 5 of them had the VHL mutation. Their mother and the siblings examined normal, and the father had passed earlier and had a family history of hypertension.

      CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma; retinal capillary hemangioma)

      CaseHPOFreeText: Presented with cerebral hemorrhage and coma at the age of 29 years. Bilateral malignant pheochromocytoma (adrenal mass resection) and retinal angiomas. Malignant pheochromocytoma confirmed with biochemical tests and pathology with involvement of liver, pancreas, kidneys and inferior vena cava.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. A clear cell renal cell carcinoma was used as positive control.

      PatientID: N/A

      KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family information provided.

      CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

      CaseHPOFreeText: Patient had VHL disease and their surgically removed tissue sample clear cell renal cell carcinoma tissue sample was used as positive control.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167Q (c.500G>A)

      LegacyVariant: p.R167Q (c.713G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

      CAID: N/A

      gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. GroupID/KindredID: 5959

      DiseaseAssertion:VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: These two patients were from the same family (5959) and both had the same VHL gene mutations.

      GroupPresentingHPOs: HP:0002666; HP:0009711; HP:0030405 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic endocrine tumor)

      GroupHPOFreeText: One patient in this family had a pheochromocytoma and cysts (type of cyst was not specified). Both patients had retinal angioma. It is unclear how many of the patients had pancreatic endocrine tumors.

      GroupNotHPOs: HP:0005584; HP:0010797 (Renal cell carcinoma, Hemangioblastoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L188V (c.562C>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: c.775C>G

      ClinVarID: 2225, https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

      CAID: N/A

      gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/3-10191569-C-G?dataset=gnomad_r2_1

      VariantEvidence: Variant reported as 775, C to G (Leu to Val), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.562C>G, p.Leu188Val (NM_000551.3).

      MutationType: missense_variant;transversion

      CivicName: L188V (c.562C>G)

      MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

    2. GroupID: 3127

      DiseaseAssertion: VHL

      GroupSize: 29

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Each group represents a family.

      GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma)

      GroupHPOFreeText: 16/29 members with pheochromocytoma, 10/29 members with CNS hemangioblastoma, 16/29 members with retinal angioma and 2/29 members with cysts. Diagnosed as a VHL Type 2A family.

      GroupNotHPOs: HP:0005584 (Renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8863170; 7759077; 8956040 (family confirmed in Zbar 1996 as Type 2 3127NCI); 7728151

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: c.505T>C

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C?dataset=gnomad_r2_1

      VariantEvidence: Variant reported as 505, T to C (Tyr to His), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.292T>C, p.Tyr98His (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. Here, we report imaging findings in a VHL patient and in 3 consecutive family members undergoing clinical and radiological screening that included [111ln-DTPA0] octreotide scintigraphy in addition to the above-mentioned procedures.

      PatientID: 2

      KindredID: 1

      Case: M, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: 4 patients from the same family (2 male 2 female; age range 27-35Y) carry this mutation (c.509T>G).

      CasePresentingHPOs: HP:0009711; HP:0002666; HP:0002668 (retinal capillary hemangioma, pheochromocytoma, paraganglioma)

      CaseHPOFreeText: scans showed he was affected by retinal angiomas, bilateral adrenal pheochromocytoma, 2 intra-foraminal masses at the S1 level (suggestive of sacral paragangliomas), and a solid hypervascular lesion in the right carotid region (indicative of intercarotid paraganglioma).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V170G (c.509T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756196 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170G (c.509T>G)

      MultipleGeneVariants: N/A

    1. p.Arg161X67M+CHB, RCC, pancreatic cyst

      PatientID: 6

      KindredID: 4

      Case: M, 67Y0M, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: Familial VHL mutation - Patient and their 4 relatives harbored p.Arg161X mutation - all with the same phenotypes hemangioblastoma, renal cell carcinoma and pancreatic cysts

      CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737 (hemangioblastoma; renal cell carcinoma; pancreatic cysts)

      CaseHPOFreeText: With an age of diagnosis of VHL at 67

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

      PreviouslyPublished: N/A

      SupplementalData: Yes

      Variant: p.R161* (c.481C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: R161* (c.481C>T)

      MultipleGeneVariants: N/A

    1. GroupID: IV (from Hemangioma VHL Associated Group)

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Studied 36 VHL-related pheochromocytoma by comparative genomic hybridization. In addition, we compared their genetic profiles with those of (1) multiple endocrine neoplasia type 2 (MEN 2)-related pheochromocytomas; (2) previously reported sporadic pheochromocytomas; and (3) VHL-related CNS hemangioblastomas.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: The patient had VHL associated hemangioblastoma (table 1).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: MEN1 and SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.C162W (c.486C>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.C162W (c.699C>G)

      ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: C162W (c.486C>G)

      MultipleGeneVariants: N/A

    1. 193T>C Ser65Pro Germline mutation

      PatientID: 7

      KindredID: 7

      Case: Age, sex, ethnicity unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65P (c.193T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 547829 https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

      CAID: N/A

      gnomAD: 

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65P (c.193T>C)

      MultipleGeneVariants: N/A

    1. Grand cousin 1–22–23Renal cysts

      PatientID: None (Grand Cousin 1)

      KindredID: G

      Case: Sex Unknown, 23Y0M, Hungarian

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

      CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005562 (Hemangioblastoma, Retinal capillary hemangioma, Multiple renal cysts)

      CaseHPOFreeText: Presented with CNS hemangioblastoma at age 22 and retinal hemangioblastoma at age 23. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 18416845

      SupplementalData: N/A

      Variant: p.S80I (c.239G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

      MutationType: missense_variant;transversion

      CivicName: S80I (c.239G>T)

      MultipleGeneVariants: N/A

    1. recognized in a large family that originated in Newfoundland but has some members who live in New Brunswick and Ontario. A collaborative investigation was begun in 1982 to document the number of affected members and the extent of their disease and to improve management of the disease. The condition has been documented in 38 members of the family, 28 living and 10 dead. The most common manifestations are retinal angioma (present in 60% of the gene carriers) and pheochromocytoma (present in 53%). Of the 28 living affected members 14 had been identified before the study began. Only 3 of the 14 patients in whom the disease was subsequently diagnosed presented with symptoms; in the remaining 11 the condition was detected by routine screening. Overall the mean age at the time of diagnosis was 23 years; in the 21 affected members of the fourth generation it was 18 years.

      PatientID: IV-50

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-50) appears to have inherited this disease from his mother. See Fig. 1 for family pedigree.

      CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)

      CaseHPOFreeText: This member was examined in St. Johns at the Memorial University of Newfoundland. The patient had pheochromocytoma and retinal angiomas, further details were not provided. He also presented with Vitamin-D-Resistant rickets, likely inherited from his mother, and non-VHL affected grandmother.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 55

      KindredID: N/A

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S3 describes 9 patients with splice mutations, including this patient.

      Variant: c.464-1G>C

      LegacyVariant: c.677-1G>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223220, https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.464-1G>C)

      MultipleGeneVariants: N/A

    1. III - 8

      PatientID: III:8

      KindredID: 1

      Case: F, 45Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: patent had bilateral pheo with an age of onset at 26Y, and operation was performed at 30Y

      CaseNotHPOs: HP:0006880; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (cerebellar hemangioblastoma, pancreatic endocrine tumor, pancreatic cysts, renal cysts, paraganglioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R167W (c.499C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

      CAID: N/A

      gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

      VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. Due to recurrent hemangioblastomas, a29-year-old patient without familial history of VHL disease was diagnosed to be at risk for the disease. Histopathological examination of a small renal mass identified a clear cell tumor with a G1 grading. Genetic characterization of the germline and of the renal tumor was performed. Polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL gene identified a deletion of a single nucleotide in exon 2 in the patient's germline and in the tumor, but not in the DNA of his parents. This deletion therefore must be a de novo mutation. Comparative genome hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of the G1 tumor with differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p and of the 3p26 signals, respectively. In conclusion, we identified a de novo germline mutation in the VHL gene of a young patient and a somatic chromosome 3p loss at the homologous chromosome 3 in his renal tumor. Our results suggest a recessive mode of inactivation of the VHL gene, providing solid evidence for its tumor-suppressor gene characteristics. Our data show the diagnostic potential of genetic testing, especially in patients without VHL family history. Furthermore, the findings of homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.

      PatientID: Proband

      KindredID: 1

      Case: M, 29Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No other family members presented with any signs of VHL disease. The patient’s aunt died from breast cancer at 46Y, the grandfather died of leukemia at 56Y.

      CasePresentingHPOs: HP:0009713; HP:0006770; HP:0001737; HP:0005562 (Spinal hemangioblastoma, Clear cell renal cell carcinoma, Pancreatic cysts, Multiple renal cysts)

      CaseHPOFreeText: Presented with recurrent spinal hemangioblastomas. Ultrasonography and computed tomography showed pancreatic and renal cysts and a renal mass. Histology after surgery to resent the renal tumor showed clear cell renal cell carcinoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F148Lfs*11 (c.444del)

      LegacyVariant: c.653del

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223212, https://www.ncbi.nlm.nih.gov/clinvar/variation/223212/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Sequencing revealed one nucleotide was deleted from the pentameric thymidines nucleotides 653–657 of exon 2 of the VHL gene, predicted to result in a stop codon, in both constitutional blood and tumor samples. All other family members tested, including his 34-year-old sister, did not show any alteration of the gene, either by SSCP analysis or by sequencing. Based on the description of the pentameric thimidines at 653-657, it was concluded that the authors reported the variant according to legacy nomenclature (AF010238.1). This was mapped to p.Phe148Leufs*11 (c.444del) according to the reference sequence NM_000551.3. Homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: F148Lfs*11 (c.444del)

      MultipleGeneVariants: N/A

    1. P1 who has developed three tumours (Figure 1a) presents a mosaic VHL mutation (c.500G>A, p.(R167Q)) with a frequency of the mutated allele of 5.7%

      PatientID: 1

      KindredID: 1

      Case: M, 17Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: None

      CohortInfo: Eight patients whose pheochromocytomas were suggestive of VHL but were negative for a VHL abnormality both by PCR-Sanger sequencing and by quantitative multiplex PCR of short fluorescent fragments (QMPSF).

      CasePresentingHPOs: HP:0010797, HP:0002666, HP:0030405, HP:0006748 (Hemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumor, adrenal pheochromocytoma)

      CaseHPOFreeText: Patient developed hemangioblastoma at age 16. At age 17 he developed right pheochromocytoma, pancreatic endocrine tumour, and a small left adrenal nodule later stated to be an adrenal pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.

      SupplementalData: N/A

      Variant: p.R167Q (c.500G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

      CAID: N/A

      gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

      VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 5.7%.

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500 G >A)

      MultipleGeneVariants: N/A

    1. GroupID: None

      DiseaseAssertion: Pancreatic cancer

      GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

      GroupInfo: N/A

      GroupPresentingHPOs: HP:0002894 (Neoplasm of the pancreas)

      GroupHPOFreeText: N/A

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S111I (c.332G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText:

      ClinVarID: 223185, https://www.ncbi.nlm.nih.gov/clinvar/variation/223185/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Unclear if the variant is somatic or germline. Unclear if this variant is found in a single person or a family/group. Accession number: H971583.

      MutationType: missense_variant;transversion

      CivicName: S111I (c.332G>T)

      MultipleGeneVariants: N/A

    1. PatientID: Proband 8

      KindredID: 4

      Case: M, 29Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666; HP:0005562 (Pheochromocytoma, Multiple renal cysts)

      CaseHPOFreeText: Unilateral PCC diagnosed at 29Y and bilateral renal cysts. Stated as having VHL type IIB.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P138Afs*6 (c.410dup)

      LegacyVariant: 623insTTTGTtG

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup

      gnomAD: N/A

      VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.

      MutationType: insertion; plus_1_frameshift_variant

      CivicName: P138fs (c.410dup)

      MultipleGeneVariants: N/A

    1. Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%.

      PatientID: 26

      KindredID: F

      Case: Sex Unknown, 30Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: assumed VHL

      FamilyInfo: No family history of VHL or pheochromocytoma

      CasePresentingHPOs: HP:0006880; HP:0000107; HP:0005584 (cerebellar hemangioblastoma, renal cyst, renal cell carcinoma)

      CaseHPOFreeText: Symptomatic by 30Y, clinically manifested as 1 recurrent cerebellar hemangioblastoma, renal cyst, bilateral renal cell carcinoma

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 20064270

      SupplementalData: N/A

      Variant: p.P86S (c.256C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 178692 https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P86S(c.256C>T)

      MultipleGeneVariants: N/A

    1. P13PCC VHL c.374A>C

      PatientID: P13

      KindredID: 10

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.H125P (c.374A>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223201 https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: H125P (c.374A>C)

      MultipleGeneVariants: N/A

    1. PatientID: V-25

      KindredID: 2

      Case: F, Age Unknown, German

      DiseaseAssertion: VHL

      FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7759077

      SupplementalData: N/A

      Variant: p.Y98H (c.292T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

      CAID: N/A

      gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. The single patient with the VHL missense mutation (case 1) had his first tumor diagnosed at age 8. He presented initially with a left adrenal pheochromocytoma, which was resected. Recurrent disease was diagnosed at age 26, at which time testing of the VHL gene was carried out.

      PatientID: 1

      KindredID: 1

      Case: M, 26Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: First tumor diagnosed at age 8. He presented initially with a left adrenal pheochromocytoma, which was resected. Recurrent disease was diagnosed at age 26, at which time testing of the VHL gene was carried out.

      CaseNotHPOs: HP:0100006; HP:0000478; HP:0009726 (Neoplasm of the central nervous system, Abnormality of the eye, Renal neoplasm)

      CaseNotHPOFreeText: Opthalmological examinations and imaging studies for lesions in the central nervous system, kidneys and organ systems failed to reveal any evidence of VHL syndrome.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table 1

      Variant: p.V84M (c.250G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 428813, https://www.ncbi.nlm.nih.gov/clinvar/variation/428813/

      CAID: N/A

      gnomAD: 0.000004376, https://gnomad.broadinstitute.org/variant/3-10183781-G-A

      VariantEvidence: Mutation was already established. Genotyping information not available.

      MutationType: missense_variant;transition

      CivicName: V84M (c.250G>A)

      MultipleGeneVariants: N/A