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    1. EIP21–––Renal cysts, renal cell carcinoma, and CNS hemangioblastomas in family members1

      PatientID: IP (Proband)

      KindredID: E

      Case: M, 21Y0M, Hungarian

      DiseaseAssertion: VHL

      FamilyInfo: Index patient was a 21-year-old man who had bilateral renal masses and renal cysts. Family history indicated a high suspicion for VHL disease, as his mother was operated for renal cell carcinoma, his uncle had spinal cord tumor, and his grandmother underwent operation for renal cell carcinoma. However, detailed clinical evaluation could not be performed in family members.

      CasePresentingHPOs: HP:0005584; HP:0005562 (Renal cell carcinoma, Multiple renal cysts)

      CaseHPOFreeText: Presented with bilateral highly vascularized renal masses and a large number of renal cysts. Diagnosed with VHL Type 1. Renal masses are noted as renal cell carcinoma in Table 1.

      CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F119Qfs*12 (c.354_355del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA915940709, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.354_355del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion; minus_2_frameshift_variant

      CivicName: F119fs (c.354_355del)

      MultipleGeneVariants: N/A

    1. A missense germline mutation in exon 1of the VHL gene was identified in the patient (p. Asp92Gly). The patient's family members (parents and 2 daughters aged 10 and 5 yr) then underwent genetic testing. The mutation was found in the youngest daughter. Full evaluation of the positive carrier did not reveal any tumor localization.

      PatientID: None (daughter)

      KindredID: 1

      Case: F, 5Y0M, ethnicity unknown

      DiseaseAssertion: asymptomatic

      FamilyInfo: The patient's family members (grandparents, mother (33Y0M; Case 1) and sister (10Y0M) underwent genetic testing. Sister and grandparents were not positive, however mother was found positive with the same mutation.

      CasePresentingHPOs: None

      CaseHPOFreeText: Full evaluation did not reveal any tumor localization.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D92G (c.275A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA351750765 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275A%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: D92G (c.275A>G)

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: F31

      Case: Sex unknown, 19Y0M, Spanish

      DiseaseAssertion: assumed VHL

      FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

      CasePresentingHPOs: HP:0009711; HP:0009713; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

      CaseHPOFreeText: Age of onset is 19Y0M.

      CaseNotHPOs: HP:0006770;HP:0002666 (clear cell renal cell carcinoma, pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D126Efs*6 (c.377_378insG)

      LegacyVariant: g.5429_5430insG

      CaseProblemVariantFreeText: Patient was reported with the g. (genomic) coding positions. The g.5429_5430insG variant worked out to correspond with c.377_378insG.

      ClinVarID: N/A

      CAID: CA2499307020 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307020

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: D126fs* (c.377_378insG)

      MultipleGeneVariants: N/A

    1. Table 1

      PatientID: N/A

      KindredID: 19

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patient had VHL disease type 1 (see table 1).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9829911

      SupplementalData:  N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: 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: Variant reported as c.226_228del and was mapped to c.227_229del.

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    2. Table 1

      PatientID: N/A

      KindredID: 17

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

      CasePresentingHPOs: HP:0006880; HP:0011513; HP:0001737; HP:0000107; HP:0006770 (Cerebellar hemangioblastoma, retinal cavernous angioma, pancreatic cyst, renal cyst, clear cell renal cell carcinoma)

      CaseHPOFreeText: Patient had VHL disease type 1: CNS-HB, RA, ccRCC, PC, KCy, and parental mosaicism (see table 1). Previously published 2000 paper (106311387) reports patient as a 48Y female.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 10631138

      SupplementalData:  N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: 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: Variant reported as c.226_228del and was mapped to c.227_229del.

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    1. exon3-codon 170 GTC->GGC with a p.Val170Gly substitution

      A 13-year-old boy was screened for a VHL mutation at 7-years-old upon identification of a missense V170G(c.509T>G) variant in the patient's father. Genetic screening of the patient also revealed that he was a carrier of same mutation as his father, but without expression of the disease at diagnosis. The father had been operated on for a bilateral pheochromocytoma at 12 years old. Upon diagnosis, annual follow ups were performed on the patient and appeared normal. At 13-years-old the patient was rushed to the hospital due to polyuria, headache, flushes, and abnormal perspiration. Abdominal ultrasonography revealed an adrenal gland tumor. His vitals were monitored and high blood pressure was treated with antihypertensive bitherapy combining an α- and β-blocker (labetalol) with a calcium antagonist (nicardipine). An MRI confirmed that the adrenal gland tumour was compatible with a pheochromocytoma. Adrenalectomy was performed, followed by slowly weaning the patient of the medications. At the last follow up 2 years after surgery, there has been no recurrence.

    1. The cytosine replaced the 716th guanine on four patients and three carriers of virulence gene from the first family, which made the 168th serine replaced by threonine.

      PatientID: III-6

      KindredID: 1

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: CNS Hemangioblastoma

      FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S168T (c.503G>C)

      LegacyVariant: p.S168T (c.716G>C)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S168T (c.503G>C)

      MultipleGeneVariants: N/A

    1. 1729Fnt 439-441 del TTC, del PheP, 26007

      PatientID: 17

      KindredID: 6007

      Case: F, 31Y9M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: She presented with 1 radiographic pancreatic neuroendocrine tumor diagnosed at age 29Y. Follow up 33M after WP surgery, currently no evidence of disease.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del (c.227_229delTCT)

      LegacyVariant: p.delF (c.439_441delTTC)

      CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

      ClinVarID: N/A

      CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    1. 194C>T Ser65Leu Germline mutation

      PatientID: 30

      KindredID: 30

      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.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) AND L89P (c.266T>A)

      MultipleGeneVariants: Somatic, VHL, c.266T>A (p.Leu89Pro)

    2. 477-478insCA Frameshift Germline mutation

      PatientID: 50

      KindredID: 50

      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.E160Qfs*11 (c.477_478insCA)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA645525053 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.477_478insCA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_2_frameshift_variant

      CivicName: K159fs (c.477_478insCA)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 9

      Case: F, 22Y0M, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: No familial/syndromic (FS) association

      CasePresentingHPOs: HP:0002666; HP:0002668 (pheochromocytoma, paraganglioma)

      CaseHPOFreeText: Sympathetic PGL with an onset of 11Y0M and a benign bilateral pheochromocytoma at 22Y0M

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

      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.500G>A)

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: 10

      Case: F, 9Y0M, Ethnicity unknown

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: Familial/syndromic (FS) association

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Benign bilateral metachronous pheochromocytoma at age 6Y0M

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

      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: 422

      KindredID: 422

      Case: Sex Unknown, 49Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: CNS hemangioblastoma.

      CaseNotHPOs: HP:0009711; HP:0006770; HP:0002666; HP:0001732; HP:0000107 (Retinal capillary hemangioma, Clear cell renal cell carcinoma, Pheochromocytoma, Abnormality of the pancreas, Renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 17024664

      SupplementalData: Table S1, S2 and S3

      Variant: p.L135Yfs*24 (c.404del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432421852, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: L135fs (c.404del)

      MultipleGeneVariants: N/A

    2. PatientID: 221

      KindredID: 221

      Case: Sex Unknown, 16Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Hemangioblastoma, Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 17006605

      SupplementalData: Table S1, S2 and S3

      Variant: c.-61_-51dup

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 517152, https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

      CAID: N/A

      gnomAD: 0.00009581, https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG?dataset=gnomad_r2_1

      VariantEvidence: Variant was reported as c.-65_-55dup11 which was mapped to c.-61_-51dup.

      MutationType: splice_site_variant; duplication; plus_2_frameshift_variant; 5_prime_UTR_variant

      CivicName: c.-61_-51dup11

      MultipleGeneVariants: N/A

    3. PatientID: 398

      KindredID: 398

      Case: Sex Unknown, 28Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0001732 (Hemangioblastoma, Abnormality of the pancreas)

      CaseHPOFreeText: CNS hemangioblastoma and pancreatic cyst or tumor.

      CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107; HP:0009711 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished:N/A

      SupplementalData: Table S1, S2 and S3

      Variant: Exon 2 Deletion (c.341-?_463+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant; deletion

      CivicName: Exon 2 Deletion

      MultipleGeneVariants: N/A

    4. In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The V155G (c.464T>G) germline mutation of the VHL gene was found in a 43 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 2). Parents, siblings and nephew were negative for the mutation confirming that this variant was de novo in the proband. No phenotype details are noted for these family members.

    5. In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The N141Ifs*12 (c.422_440del) germline variant of the VHL gene was found in a 23 year old patient (ID 80) presenting with CNS hemangioblastoma and renal cystic lesion. Parents were negative for the mutation, confirming it as de novo in the proband. No phenotype details are noted for these family members.

    6. PatientID: 223

      KindredID: 223

      Case: Sex Unknown, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Positive family history for VHL.

      CasePresentingHPOs: HP:0000107, HP:0010797 (renal cyst, hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0001737, HP:0002666, HP:0006770, HP:0009711 (pancreatic cysts, pheochromocytoma, clear cell renal cell carcinoma, retinal capillary hemangioma )

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2, S3.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

      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

    7. PatientID: 122

      KindredID: 122

      Case: Sex Unknown, 31Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished:N/A

      SupplementalData: Table S1, S2 and S3

      Variant: Partial Deletion (8.2kb)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion

      CivicName: Partial deletion of 8.2kb

      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: 6CE

      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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 6CE. 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.S183* (c.548C>A)

      LegacyVariant: p.S183* (c.761C>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

      CAID: N/A

      gnomAD: N/A

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

      MutationType: stop_gained

      CivicName: S183* (c.548C>A)

      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: 11YO

      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 11YO. 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.C162Y (c.485G>A)

      LegacyVariant: p.C162Y (c.698G>A)

      CaseProblemVariantFreeText: N/A

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

      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: C162Y (c.485G>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: 133CA

      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 133CA. 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.G114C (c.340G>T)

      LegacyVariant: p.G114C (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>T

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: G114C (c.340G>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: 43CA

      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 43CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL families 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.V66* (c.196delG)

      LegacyVariant: p.V66* (c.409delG)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432536396 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.196delG

      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: V66* (c.196delG)

      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: 2547NCI

      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 2547NCI. 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.G93D (c.278G>A)

      LegacyVariant: p.G93D (c.491G>A)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496054 https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: G93D (c.278G>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: R-D

      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 Utrecht, The Netherlands database, with an unknown number of members belonging to Family ID R-D. 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: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.V170D (c.722T>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

    7. 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

    8. 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

    1. HIGH GRADE VON HIPPEL-LINDAU SYNDROME PRESENTING WITH BILATERAL PHEOCHROMOCYTOMA IN A CHILD

      PatientID: N/A (case)

      KindredID: 1

      Case: M, 9Y0M, Ethnicity Unknown

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: The parents and siblings were negative for the gene mutation thus indicating that our patient has a De novo mutation.

      CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

      CaseHPOFreeText: previously healthy male presented with hypertension, increasing BMI despite decreased height and weight, last three years. His ultrasound was abdominal showing bilateral suprarenal masses. An abdominal MRI confirmed the finding of bilateral adrenal masses measuring 3 x 2.7 x 2.5 cm in the right and 3.6 x 3.5 x 2.7 cm in the left. He underwent a bilateral adrenalectomy and pathology resulted as bilateral pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V166F (c.496G>T)

      LegacyVariant: p.V166F

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2224 https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: N/A

      MultipleGeneVariants: N/A

    1. c.500 G>Aap.R167Q

      GroupID: 25B

      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: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 5 patients with the given mutation were grouped as group 25(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: N/A

      GroupPreviousTesting: 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

    2. c.488 T>Aap.L163H

      GroupID: 23A

      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.L163H (c.488T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756137 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: L163H (c.488T>A)

      MultipleGeneVariants: N/A

    3. c.364_365 GC>ATp.A122I

      GroupID: 12B

      Case: Sex, Age, Ethnicity unknown

      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.

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

      CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.A122I (c.364_365delinsAT)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: Authors report this as: c.364_365GC>AT; which can be translated to c.364_365delinsAT

      ClinVarID: N/A

      CAID: CA658820874 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.364_365delinsAT

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: delins

      CivicName: A122I (c.364_365delinsAT)

      MultipleGeneVariants: N/A

    4. c.488 T>Aap.L163H

      GroupID: 23B

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

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 2 patients with the given mutation were grouped as group 23(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: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L163H (c.488T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756137 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: L163H (c.488T>A)

      MultipleGeneVariants: N/A

    5. c.340 G>Aap.G114S

      GroupID: 8B

      Case: Sex, Age, Ethnicity unknown

      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.

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

      CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: 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

    6. c.340 G>Aap.G114S

      GroupID: 8A

      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.G114S (c.340G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: 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

    7. c. 593 T>Aap.L198Q

      GroupID: 29A

      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.L198Q (c.593T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 1066145 https://www.ncbi.nlm.nih.gov/clinvar/variation/1066145/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: L198Q (c.593T>A)

      MultipleGeneVariants: N/A

    8. c.482 G>Aap.R161Q

      GroupID: 22B

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

      GroupSize: 8

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 8 patients with the given mutation were grouped as group 22(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: 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

    9. 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

    1. PatientID: None

      KindredID: 1

      Case: M, 46Y0M, Spanish

      DiseaseAssertion: VHL

      FamilyInfo: No familial antecedents and no known familial tumors.

      CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

      CasePresentingHPOs: HP:0000107; HP:0006880; HP:0006770; HP:0010797 (Renal cyst, Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Hemangioblastoma)

      CaseHPOFreeText: Medullar hemangioblastoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Exon 2-3 Deletion (c.341-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Germline HSPC300 retention. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

      MutationType: exon_loss_variant

      CivicName: Exon 2-3 Deletion

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: 67

      Case: M, 25Y0M, Spanish

      DiseaseAssertion: VHL

      FamilyInfo: No familial antecedents. No known familial tumors.

      CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

      CasePresentingHPOs: HP:0006880; HP:0001737; HP:0009711 (Cerebellar hemangioblastoma, Pancreatic cysts, Retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Exon 1-2 Deletion (c.1-?_464+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Germline HSPC300, ENST197804 and FANCD2 (unclear if partial or complete) gene deletion. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

      MutationType: exon_loss_variant

      CivicName: Exon 1-2 Deletion

      MultipleGeneVariants: Germline, HSPC300, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, FANCD2, Deletion

    1. PatientID: None

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: His brother and grandfather had the same VHL mutation. His mother also had this mutation and presented with pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, and spinal hemangioblastoma.

      CohortInfo:Three patients with endolymphatic sac tumors were studied.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.464-1G>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

      ClinVar: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.464-1G>A)

      MultipleGeneVariants: N/A

    1. Case 2. A 33-year-old male patient (who is the first cousin of Case 1) was referred to the retina department. He was operated on because of a CNS hemangioblastoma 3 years earlier (Figure 4). The patient stated that he had vision loss in his left eye after the CNS operation. About 2 weeks earlier, a partial right nephrectomy operation was performed due to RCC (Figure 5).Open in a separate windowFigure 4Preoperative and postoperative magnetic resonance images of the CNS haemangioblastoma (Case 2).Open in a separate windowFigure 5Abdominal computerized tomography image of Case 2. Renal cell carcinoma in the right kidney (preoperatively).Best-corrected visual acuity was 1.0 on the Snellen acuity chart in the right eye and no light perception in the left eye. Biomicroscopic examination was normal in both eyes. The fundus examination revealed optic nerve atrophy and two RH at the equator in the left eye, and was normal in the right eye. Fundus fluorescein angiography showed that hyperfluorescence and fluorescein leakage was caused by the lesions. Hyper reflectance was observed under the cross-section of the RH, and the macular section was normal in OCT (Figure 6). The same mutation as in Case 1 was also detected in the genetic analysis (c.202T>C, p.Ser

      PatientID: None

      KindredID: 1

      Case: M, 33Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: First cousin (male, 29Y, proband) presented with renal cell carcinoma, vitritis, retinal capillary hemangioma and retinal detachment. The proband also had the germline mutation found in his cousin.

      CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0000648; HP:0000572 (Renal cell carcinoma, Hemangioblastoma, Retinal capillary hemangioma, Optic atrophy, Visual loss)

      CaseHPOFreeText: He was operated on because of a CNS hemangioblastoma 3 years earlier. The patient stated that he had vision loss in his left eye after the CNS operation. About 2 weeks earlier, a partial right nephrectomy operation was performed due to RCC. The fundus examination revealed optic nerve atrophy and two RH (determined to be the cause of vision loss) at the equator in the left eye, and was normal in the right eye.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S68P (c.202T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA16621912, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA16621912

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S68P (c.202T>C)

      MultipleGeneVariants: N/A

    1. 3 large gene rearrangements.

      PatientID: 3

      KindredID: 76

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666; HP:0030405; HP:0005584 (pheochromocytoma, pancreatic endocrine tumour, renal cell carcinoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: NONE (unspecified large rearrangement)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: rearrangement_region

      CivicName: rearrangement

      MultipleGeneVariants: N/A

    2. 3 large gene rearrangements

      PatientID: 2

      KindredID: 40

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666; HP:0030405; HP:0005584 (pheochromocytoma, pancreatic endocrine tumour, renal cell carcinoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: NONE (unspecified large rearrangement)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: rearrangement_region

      CivicName: rearrangement

      MultipleGeneVariants: N/A

    3. 5 nonsense mutations

      Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. A germline nonsense mutation (c.525C>A) was found in patient no. 35 from family 7, presenting with pancreatic endocrine tumour. No family history was discussed.

    4. 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. 583FemaleIYesAGND* AGLOH (G)

      PatientID: 5

      KindredID: 5

      Case: F, 83Y0M, Taiwanese (East-Asian)

      DiseaseAssertion: renal cell carcinoma

      FamilyInfo: N/A

      CohortInfo: 8 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs1642742 in VHL (c.*294G>A). All but one of these patients (7/8) also presented with the germline variant rs779805 (c.-195G>A) in VHL.

      CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

      CaseHPOFreeText: She had stage I clear cell renal cell carcinoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 21982469

      SupplementalData: Yes - Additional file 1: Figure S1

      Variant: c.*294G>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 342407 https://www.ncbi.nlm.nih.gov/clinvar/variation/342407/

      CAID: N/A

      gnomAD: 0.5911 https://gnomad.broadinstitute.org/variant/3-10191943-G-A

      VariantEvidence: Heterozygous for both, she also presented with the germline variant c.-195G>A in VHL. LOH (G) of this mutation was found in the tumor tissue as well

      MutationType: 3_prime_UTR_variant

      CivicName: c.-195G>A AND c.*294G>A

      MultipleGeneVariants: Germline, VHL, c.-195G>A

    2. 277FemaleIYesAGLOH (A)AGLOH (A)

      PatientID: 2

      KindredID: 2

      Case: F, 77Y0M, Taiwanese (East-Asian)

      DiseaseAssertion: renal cell carcinoma

      FamilyInfo: N/A

      CohortInfo: 7 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs779805 (c.-195G>A) in VHL. All of these patients also presented with the germline variant rs1642742 in VHL (c.*294G>A).

      CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

      CaseHPOFreeText: She had stage I clear cell renal cell carcinoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 21982469

      SupplementalData: Yes - Additional file 1: Figure S1

      Variant: c.-195G>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 342397 https://www.ncbi.nlm.nih.gov/clinvar/variation/342397

      CAID: N/A

      gnomAD: 0.5796 https://gnomad.broadinstitute.org/variant/3-10183337-G-A

      VariantEvidence: RFLP analysis was used to screen for the allele genotype by BsaJ I digestion methods. Heterozygous for both, she also presented with the germline variant c.*294G>A in VHL. LOH (A) of both mutations was found in the tumor tissue as well

      MutationType: 5_prime_UTR_variant

      CivicName: c.-195G>A AND c.*294G>A

      MultipleGeneVariants: Germline, VHL, c.*294G>A

    3. 166FemaleIIIYesAGLOH (G)AGLOH (G)

      PatientID: 1

      KindredID: 1

      Case: F, 66Y0M, Taiwanese (East-Asian)

      DiseaseAssertion: renal cell carcinoma

      FamilyInfo: N/A

      CohortInfo: 8 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs1642742 in VHL (c.*294G>A). All but one of these patients (7/8) also presented with the germline variant rs779805 (c.-195G>A) in VHL.

      CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

      CaseHPOFreeText: She had stage III clear cell renal cell carcinoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 21982469

      SupplementalData: Yes - Additional file 1: Figure S1

      Variant: c.*294G>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 342407 https://www.ncbi.nlm.nih.gov/clinvar/variation/342407/

      CAID: N/A

      gnomAD: 0.5911 https://gnomad.broadinstitute.org/variant/3-10191943-G-A

      VariantEvidence: Heterozygous for both, she also presented with the germline variant c.-195G>A in VHL. LOH (G) of both mutations was found in the tumor tissue as well

      MutationType: 3_prime_UTR_variant

      CivicName: c.-195G>A AND c.*294G>A

      MultipleGeneVariants: Germline, VHL, c.-195G>A

    1. VHL

      PatientID: 52

      KindredID: 2

      Case: Sex Unknown, 23Y0M, Norwegian

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: Yes, a family history of neuroendocrine tumor (NET). They have another family member with the same mutation and pheochromocytoma.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: Preoperatively presented with hypertension; surgery at 23Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: NF1, RET, SDHB, SDHC, SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F119S (c.356T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753715 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.356T%3EC

      gnomAD: N/A

      VariantEvidence: This mutation was found in DNA from the adjacent normal tissue, and this finding was found to be reproducible. The same VHL variant was later on observed in a family member with PHEO.

      MutationType: missense_variant;transition

      CivicName: F119S (c.356T>C)

      MultipleGeneVariants: N/A

    1. PatientID: 53

      KindredID: 53

      Case: M, 36Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: Family history 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: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.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19270817

      SupplementalData: N/A

      Variant: Exon 2-3 Deletion (c.341-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 2-3 Deletion

      MultipleGeneVariants: N/A

    2. PatientID: 5

      KindredID: 5

      Case: M, 43Y0M, 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:0005562 (Hemangioblastoma, Multiple renal cysts)

      CaseHPOFreeText: Multiple or bilateral CNS hemangioblastoma and renal cysts. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19270817 and/or 19949673

      SupplementalData: N/A

      Variant: p.E70K (c.208G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

      CAID: N/A

      gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: E70K (c.208G>A)

      MultipleGeneVariants: N/A

    1. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.

      GroupID: 33

      DiseaseAssertion: VHL

      GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

      GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

      GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Epididymal cyst)

      GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (3), Retinal capillary hemangioma (3), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (1), Epididymal cyst (1)

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Table 2, Table 1, Table 3

      Variant: Exon 3 Deletion (c.464-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 3 Deletion

      MultipleGeneVariants: N/A

    2. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families

      GroupID: 17

      DiseaseAssertion: VHL

      GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

      GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

      GroupPresentingHPOs: HP:0005584; HP:0009711; HP:0009713; HP:0030393; HP:0001737 (Renal cell carcinoma, Retinal capillary hemangioma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts)

      GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Retinal capillary hemangioma (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Pancreatic cysts (1)

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Table 2, Table 1, Table 3

      Variant: Exon 2 Deletion (c.341-?-463+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 2 Deletion

      MultipleGeneVariants: N/A

    3. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.

      GroupID: 21

      DiseaseAssertion: VHL

      GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

      GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

      GroupPresentingHPOs: HP:0005584; HP:0002666; HP:0009711; HP:0010797; HP:0009713; HP:0001737; HP:0030424 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts, Epididymal cyst)

      GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Pheochromocytoma (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Pancreatic cysts (1), Epididymal cyst (1)

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Table 2, Table 1, Table 3

      Variant: Exon 2-3 Deletion (c.341-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 2-3 Deletion

      MultipleGeneVariants: N/A

    4. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.

      GroupID: 38

      DiseaseAssertion: VHL

      GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

      GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

      GroupPresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

      GroupHPOFreeText: # of affected individuals: Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (2), Spinal hemangioblastoma (2), Endolymphatic sac tumor (1), Pancreatic cysts (2), Epididymal cyst (1)

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Table 2, Table 1, Table 3

      Variant: Exon 1-3 Deletion (c.1-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 1-3 Deletion

      MultipleGeneVariants: Germline, HSPC300, partial deletion

      MultipleGeneVariants: Germline, ENST197804, deletion

    1. GroupID: 21

      Case: Age unknown, Sex Unknown, Ethnicity Unknown

      DiseaseAssertion: asymptomatic

      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: Unknown

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711; HP:0005584; HP:0002666; HP:0006880 (retinal capillary hemangioma; renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.T124Mfs*33 (c.371_377delCACACGA)

      LegacyVariant: p.T124Mfs*33 (c.369_375delGACACAC)

      CaseProblemVariantFreeText: written in paper as:c.369_375del, automaps to NM_000551.3:c.371_377del - most up to date transcript

      ClinVarID: N/A

      CAID: CA913189240 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.371_377delCACACGA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: G123fs (c.369_375delGACACAC)

      MultipleGeneVariants: N/A

    2. GroupID: 20

      Case: 19Y0M, Sex Unknown, Ethnicity Unknown

      DiseaseAssertion: retinal capillary hemangioma

      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 (retinal capillary hemangioma)

      CaseHPOFreeText: patient had retinal angiomas diagnosed at 19Y

      CaseNotHPOs: HP:0005584; HP:0002666; HP:0006880 (renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.T124Hfs*35 (c.369delG)

      LegacyVariant: p.Thr124Hisfs*35 (c.367delG)

      CaseProblemVariantFreeText: c.367delG automaps to c.369delG - most up to date transcript

      ClinVarID: N/A

      CAID: CA432421810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.369delG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: T124fs (c.369del)

      MultipleGeneVariants: N/A

    3. GroupID: 2

      DiseaseAssertion: cerebellar hemangioblastoma

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.162_163insT) was found in 1 VHL family with 2 patients.

      GroupPresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      GroupHPOFreeText: both patients had cerebellar hemangioblastomas with a mean age of diagnosis of 19Y

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

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.E55* (c.162_163insT)

      CaseProblemVariantFreeText: The mutation was written as follows: AFO10238:375_376insT; NM_000551.2:c.162_163insT; p.54MetX. Author Maher was contacted and confirmed "A single nucleotide insertion (T) was detected at position 375 (375insT)” from 2000 lab report - June 1, 2021 - therefore assume p. was transcribed incorrectly.

      LegacyVariant: p.54MetX (c.375_376insT)

      ClinVarID: N/A

      CAID: CA2499307063 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307063

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: E55* (c.162_163insT)

      MultipleGeneVariants: N/A

    4. GroupID: 64

      Case: 49Y0M, 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 (c.340G>T) was found in 1 VHL family with a single patient.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 49Y

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA351751376 http://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. large/complete deletions

      PatientID: 145

      KindredID: None

      Case: Age and Sex unknown, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: None

      CasePresentingHPOs: HP:0001737; HP:0000107; HP:0005584; HP:0030405 (pancreatic cysts, renal cyst, Renal cell carcinoma, Pancreatic endocrine tumour)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666; HP:0030393 (hemangioblastoma, Retinal capillary haemangioblastoma, Pheochromocytoma, Endolymphatic sac tumour)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; See Suppl 1 (Supporting table)

      Variant: c.464-?_642+?del

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 3 Deletion

      MultipleGeneVariants: N/A

    2. large/complete deletions

      PatientID: 140

      KindredID: None

      Case: Age and Sex unknown, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: None

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

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711; HP:0002666; HP:0030405; HP:0030393 (Retinal capillary haemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumour, Endolymphatic sac tumour)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes; See Suppl 1 (Supporting table)

      Variant: c.341-?-463+?del

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: c.341-?-463+?del

      MultipleGeneVariants: N/A

    1. PatientID: 15

      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 S5 describes 8 patients with small deletions, including this patient.

      Variant: p.L129Wfs*30 (c.384del)

      LegacyVariant: c.597delT (p.128fs)

      CaseProblemVariantFreeText: Submitted revision on CIViC for correct CIViC name: L129Wfs*30 (c.384del).

      ClinVarID: N/A

      CAID: CA70049452

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant; deletion

      CivicName: L129Wfs*?(c.383delT)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 231

      Case: Age unknown, Sex unknown, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Paper states familial VHL

      CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584 (hemangioblastoma; pancreatic cysts; renal cell carcinoma)

      CaseHPOFreeText: Patient had CNS HB, pancreatic cysts, and a Grawitz tumor

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes (Specifically Supp. Table S2)

      Variant: Exon 1-3 Deletion (c.1-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 1-3 Deletion

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: 32165

      Case: Age unknown, Sex unknown, Turkish

      DiseaseAssertion: VHL

      FamilyInfo: familial Turkish germline mutation

      CasePresentingHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)

      CaseHPOFreeText: Bilateral pheochromocytoma and CNS hemangioblastoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes

      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. PatientID: 5

      KindredID: 6

      Case: F, 40Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: The patient had a hemangioblastoma localized to the corpus callosum at age 31. After surgery the patient was alive with disease. The patient was followed up 108 months later.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Exon 3 Deletion

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType:exon_loss_variant

      CivicName: Exon 3 Deletion

      MultipleGeneVariants: N/A

    1. KindredID: 103

      GroupID: 14

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no.103 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 other phenotypic information is listed for this kindred.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S80R (c.240T>G)

      LegacyVariant: p.S151R (c.453T>G)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351750515

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S80R (c.240T>G)

      MultipleGeneVariants: N/A

    2. KindredID:71

      GroupID: 10

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no.71 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is present in this kindred.

      GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

      GroupHPOFreeText: This study investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. No other information about disease presentation within members of a kindred could be inferred.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.C77Lfs*55 (c.228dup)

      LegacyVariant: c.441insC (p.147fs)

      GroupProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795177, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.228_229insC

      gnomAD: N/A

      VariantEvidence:

      MutationType: plus_1_frameshift_variant; duplication

      CivicName: C77Lfs*55(c.228dup)

      MultipleGeneVariants: N/A

    1. PatientID: Proband 6

      KindredID: 2

      Case: F, 28Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Mother, aunt and aunt’s cousin (all relative to proband 6) had this variant. Mother and proband presented with unilateral pheochromocytoma and aunt and aunt’s cousin were asymptomatic. Proband also presented with a renal cyst and hypertension.

      CasePresentingHPOs: HP:0002666; HP:0000107; HP:0000822 (Pheochromocytoma, Renal cyst, Hypertension)

      CaseHPOFreeText: Unilateral PCC diagnosed at 28Y and unilateral renal cyst and hypertension. Stated as having VHL type IIC.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R120T (c.359G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753738, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.359G%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R120T (c.359G>C)

      MultipleGeneVariants: N/A

    1. PatientID: 2

      KindredID: 2

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: CNS hemangioblastoma and RCC.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 10761708

      SupplementalData: N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: codon 147 (c.440delTCT)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

      gnomAD: N/A

      VariantEvidence: Nucleotide deletion (i.e. 440delTCT) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.227_229del (NM_000551.3).

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    2. Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported variants in legacy variant nomenclature (AF010238.1) so this variant was mapped to c.429_439del (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 26 had a G144fs (c.429_439del) frameshift mutation. 1 member was affected with retinal angioma, CNS hemangioblastoma, and renal cell carcinoma. Other demographics of the members were not described.

    3. GroupID: 14

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A GroupEthnicity: Japanese GroupAgeRange: N/A

      GroupInfo: The 2 patients are grouped based on both having the same mutation. They are unrelated to one another.

      GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

      GroupHPOFreeText: 2/2 patients in this group presented with RCC.

      GroupNotHPOs: HP:0009711; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 10761708

      SupplementalData: N/A

      Variant: p.R120Nfs*40 (c.358_359insAC)

      LegacyVariant: codon 191 (c.571insAC)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573106245, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA2573106245

      gnomAD: N/A

      VariantEvidence: Nucleotide deletion (i.e. 571insAC) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.358_359insAC (NM_000551.3).

      MutationType: insertion; plus_2_frameshift_variant

      CivicName: R120fs (c.358_359insAC)

      MultipleGeneVariants: N/A

    1. Case III:1 (the proband’s son)

      PatientID: III:1

      KindredID: 1

      Case: M, 6Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Case III:1 (this patients mother) was a 32 year old female who complained of blurred vision for the past 2 years in her left eye. Fundus examinations showed several retinal hemangioblastomas in the temporal area of the left eye. They had previously undergone the operation for cerebellar hemangioblastoma 3 years prior. Case III:2 (this patient’s sister) was a 12 year old female who complained of a curtain coming across the vision in her left eye during the screening examination. Fundus examinations revealed a small hemangioblastoma in the infratemporal region of the peripheral retina in her right eye. A sizeable hemangioblastoma with 2.5 papilla diameters and prominant feeder vessels were detected in the inferior peripheral retina of her left eye. Case I:2 (this patient’s grandmother) had blindness in one eye and died of renal carcinoma, genetic testing was not preformed on this patient. Pedigree: see Figure 1.

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: Fundus examination revealed a very small hemangioblastoma in the distant peripheral retina of his right eye, while his left eye was normal.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W117R (c.349T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753664 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_transversion

      CivicName: W117R (c.349T>A)

      MultipleGeneVariants: N/A

    1. ProbandMale

      PatientID: 3

      KindredID: 3

      Case: M, 24Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: (See figure 3C for pedigree). Family history of VHL. The proband (Patient 3) of family 3 was a 24-year-old male who presented with adrenal pheochromocytomas and a cyst in his left kidney. The proband's family history of VHL included a mother and aunt who died from brain hemangiomas, a sister with pheochromocytomas in her bilateral adrenals and a female cousin with pheochromocytomas in her right adrenal.

      CasePresentingHPOs: HP:0006748, HP:0000107 (Adrenal pheochromocytoma, Renal cyst)

      CaseHPOFreeText: Masses in his bilateral adrenals (pheochromocytomas). In February 2013, he underwent an abdominal CT scan that revealed masses in his bilateral adrenals (Fig. 1C, upper image) and a cyst in his left kidney.

      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?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. X214L one case (female)

      PatientID: None

      KindredID: 2

      Case: F, 38Y0M, Ethnicity Unknown

      DiseaseAssertion: Retinal hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711 (Retinal hemangioblastoma)

      CaseHPOFreeText: The patient was diagnosed with bilateral retinal hemangioblastoma at an unknown age.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.*214Lext*14(c.641G>T)

      LegacyVariant: N/A

      ClinVarID: 223236, http://www.ncbi.nlm.nih.gov/clinvar/variation/223236

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_loss

      CivicName: *214Lext*14(c.641G>T)

      MultipleGeneVariants: N/A

    2. 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. PatientID: 1

      KindredID: 48

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

      CaseHPOFreeText: one RCC tumor was detected in this patient

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del (c.227delTCT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.F76del (c.440delTCT)

      ClinVarID: N/A

      CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

      gnomAD: N/A

      VariantEvidence: LOH detected.

      MutationType: deletion

      CivicName: F76del (c.227delTCT)

      MultipleGeneVariants: N/A

    2. PatientID: 1

      KindredID: 54

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: another member (54/2) of the family was detected with an HB and the same mutation

      CasePresentingHPOs: HP:0006880 (hemangioblastoma)

      CaseHPOFreeText: one RCC tumor was detected in this patient

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R177Dfs*25 (c.528delG)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.176 FS (c.741delG)

      ClinVarID: N/A

      CAID: CA432423454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.528delG

      gnomAD: N/A

      VariantEvidence: LOH detected.

      MutationType: minus_1_frameshift_variant

      CivicName: R177fs (c.528delG)

      MultipleGeneVariants: N/A

    1. variants of VHL in 18 probands

      PatientID: 3

      KindredID: 3

      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.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: N/A

      VariantEvidence: N/A

      MutationType: missense_variant, transition

      CivicName: V84M (c.250G>A)

      MultipleGeneVariants: N/A

    2. 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. VHL_11Frozenc.500G>Ap.Arg167GlnF47AdrenalPCCB

      PatientID: VHL_11 (tumour ID)

      KindredID: 11

      Case: F, 47Y0M, Ethnicity Unknown

      DiseaseAssertion: Adrenal Pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at age 47.

      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

      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

    2. VHL_18FFPEc.482G>Ap.Arg161GlnMNAAdrenalPCCB

      PatientID: VHL_18 (tumor ID)

      KindredID: 18

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at an unknown age.

      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

    3. 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. GroupID: 8

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Family of 2 VHL Type 1 affected individuals.

      GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

      GroupHPOFreeText: CNS hemangioblastoma (2/2 affected members).

      GroupNotHPOs: HP:0009711; HP:0002894; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Neoplasm of the pancreas, Pheochromocytoma, Renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+7G>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573131791, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131791

      gnomAD: N/A

      VariantEvidence: Variant reported as IVS1+7G>A which is assumed to be equivalent to c.340+7G>A. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

      MutationType: splice_site_variant; missense_variant;transition

      CivicName: c.340+7G>A

      MultipleGeneVariants: N/A

    2. PatientID: None (Mother)

      KindredID: 13

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Child of this patient presented with CNS hemangioblastoma, retinal angioma, renal carcinoma and a renal tumor <3cm in size and the c.436delC germline variant of the VHL gene.

      CasePresentingHPOs: HP:0006880; HP:0009713; HP:0001737 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

      CaseHPOFreeText: This patient was originally thought to be an asymptomatic carrier but was later discovered to have two occult hemangioblastomas (spinal and cerebellar) as well as multiple pancreatic cysts.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P146Lfs*13 (c.436del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432421892, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.436del

      gnomAD: N/A

      VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: P146fs (c.436del)

      MultipleGeneVariants: N/A

    1. 6418Y18Y44NNNYNc.500G>AExon 3p.Arg167GlnMissense

      PatientID: 6

      KindredID: 4

      Case: Sex Unknown, 44Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Four other family members were found to have the same mutation (Patient 7,8,9,10).

      CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405, HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

      CaseHPOFreeText: The patient was diagnosed with pancreatic endocrine tumor at age 44 and diagnosed with pheochromocytoma and paraganglioma at age 18.

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

      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

    2. 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

    1. GroupID: 285

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 4 members of this family are reported as carrying the E52K (c.154G>A) germline variant of the VHL gene. Member 6493 had no renal involvement, member 1422 had mild renal involvement and member 6495 had moderate renal involvement (RCC) and member 6497 phenotypes were unknown. 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).

      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.E52K (c.154G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 161402, https://www.ncbi.nlm.nih.gov/clinvar/variation/161402/

      CAID: N/A

      gnomAD: 0.00008525, https://gnomad.broadinstitute.org/variant/3-10183685-G-A?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: E52K (c.154G>A)

      MultipleGeneVariants: N/A

    2. Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.H191Tfs*11 (c.571del) germline variant of the VHL gene was detected in a family (ID 51). Members 2127, 1184 and 1182 had unknown renal involvement. Member 1183 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

    3. GroupID: 7

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 4 members of this family presented with the c.525C>A germline variant of the VHL gene. Members 6548 and 6362 had unknown renal involvement. Member 6364 presented with mild renal disease. Member 6728 presented with moderate 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).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 1 individual with this mutation is reported. It is unclear which of the current family members the previously published individual corresponds to.

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

      Variant: p.Y175* (c.525C>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 1298905, https://www.ncbi.nlm.nih.gov/clinvar/variation/1298905/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion; stop_gained

      CivicName: Y175* (c.525C>A)

      MultipleGeneVariants: N/A

    4. GroupID: 237

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 2 members of this family were found to harbor a germline large rearrangement of the VHL gene. Member 7398 had no renal involvement. Member 645 presented with severe 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:0005584 (Renal cell carcinoma)

      GroupHPOFreeText: 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 12 individuals with this mutation are reported. It is unclear which of the previously reported individuals correspond to which of the currently reported families/individuals (i.e. families 40, 90, 174, 237, 264, 284, 307 or 394).

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

      Variant: Rearrangement

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: rearrangement_region

      CivicName: Rearrangement

      MultipleGeneVariants: N/A

    5. GroupID: 51

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 4 members of this family were found to harbor the c.571delC germline variant of the VHL gene. Members 2127, 1184 and 1182 had unknown renal involvement. Member 1183 presented with severe 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:0005584 (Renal cell carcinoma)

      GroupHPOFreeText: 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 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.

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

      Variant: p.H191Tfs*11 (c.571del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795182, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.571del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: H191Tfs*11 (c.571del)

      MultipleGeneVariants: N/A

    6. GroupID: 60

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe 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]). 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 and/or 9829912, where 3 individuals and 3 families 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 279.

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

      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 previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The F76del (c.227_229del) germline mutation was found in 2 VHL type 1 patients, both presenting with hemangioblastomas of the central nervous system, pancreatic cyst or tumor, and renal cell carcinoma (families ID 80 and 2). The variant was reported as c.437_439del and mapped to c.224_226del which is equivalent to c.227_229del. This family was previously reported in PMID 8634692.

    2. PatientID: None

      KindredID: 104

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: Pheochromocytoma, renal cell carcinoma, pancreatic cyst or tumor (unspecified) and retinal angioma.

      CaseNotHPOs: HP:0010797 (Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.698G>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

    3. PatientID: None

      KindredID: 48

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, renal cell carcinoma and pancreatic cyst or tumor (unspecified).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Q96_P97delinsH (c.288_290del)

      LegacyVariant: c.501_503del

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573106244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.288_290del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion; deletion

      CivicName: Q96_P97delinsH (c.288_290del)

      MultipleGeneVariants: N/A

    4. A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The Q73Rfs*86 (c.217del) germline mutation was found in a VHL type 1 patient with hemangioblastomas of the central nervous system and retinal angiomas (family ID 98). The variant was reported as c.428del and mapped to c.215del which is equivalent to c.217del.

    1. proband (III-2

      PatientID: III-2

      KindredID: 1

      Case: M, 62Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: His mother (II,2) did not carry the mutation. His father (II-1) died age 42 from a cerebellar hemangioblastoma, while his paternal grandparents died at an advanced age and had no known history of VHL manifestations. His brother (III,1) did not harbour the mutation. The patient and his wife (III,3) who did not carry the mutation, had 3 daughters; two with the mutation and one without. Two of his daughters who carried the mutation, aged 28 and 36 (IV-2, IV-3), had a personal history of CNS and retinal hemangioblastomas. Patient IV-2 recently developed a ccRCC and a pheochromocytoma, and patient IV-3 a pancreatic neuroendocrine tumor. Refer to pedigree in Figure 1.

      CasePresentingHPOs: HP:0006770, HP:0010797, HP:0009711 (clear cell renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: The patient died at age 62 of CNS complications.

      CaseNotHPOs: HP:0002666, HP:0030405 (pheochromocytoma, pancreatic endocrine tumour)

      CaseNotHPOFreeText: No erythrocytosis; the hematocrit, red blood cells count and Epo levels were all normal.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes supplemental data and figures. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Data.pdf

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Figures.pdf

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020413 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.482G%3EA

      gnomAD: N/A

      VariantEvidence: The patient was a heterozygous carrier of a single R200W and R161Q mutation (both on the same VHL allele).

      MutationType: missense_variant;transition

      CivicName: R200W (c.598C>T) and R161Q (c.482G>A)

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

    2. patient IV-3

      PatientID: IV-3

      KindredID: 1

      Case: F, 36Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Her paternal grandmother (II,2) did not carry the mutation. Her paternal grandfather (II-1) died age 42 from a cerebellar hemangioblastoma. Her uncle (III,1) did not harbour the mutation. The patient's father was the proband (III,2) and carried the mutation, presenting with clear cell renal cell carcinoma, hemangioblastoma of CNS, and retinal capillary hemangioblastoma. The mother did not carry the mutation. The patient had one unaffected sister (IV-1) and another who carried the mutation (IV-2) and had a history of pheohcromocytoma, clear cell renal cell carcinoma, hemangioblastoma of the CNS, and retinal capillary hemangioblastoma. Refer to pedigree in Figure 1.

      CasePresentingHPOs: HP:0030405, HP:0010797, HP:0009711 ( pancreatic endocrine tumour, hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0006770, HP:0002666 (clear cell renal cell carcinoma, pheochromocytoma )

      CaseNotHPOFreeText: No erythrocytosis; the hematocrit, red blood cells count and Epo levels were all normal.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes supplemental data and figures. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Data.pdf

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555745/bin/NIHMS881280-supplement-Supplemental_Figures.pdf

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020413 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.482G%3EA

      gnomAD: N/A

      VariantEvidence: The patient was a heterozygous carrier of a single R200W and R161Q mutation (both on the same VHL allele).

      MutationType: missense_variant;transition

      CivicName:R200W(c.598C>T) and R161Q(c.482G>A)

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

    1. II 4 5 No manifestations M c.388G > A (p.Val130Ile)

      PatientID: II

      KindredID: 2

      Case: Sex Unknown, 5Y0M, Danish

      DiseaseAssertion: Asymptomatic

      FamilyInfo: One other family member presented with his VHL mutation and was asymptomatic.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Diagnosed with VHL at age 4Y. Age at the end of study: 5Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V130I (c.388G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753916, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: V130I (c.388G>A)

      MultipleGeneVariants: N/A

    1. PatientID: VI-17

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL (Asymptomatic)

      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: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0002668 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma, Paraganglioma)

      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. c695G→A, R161Q mutation was identified in two unrelated kindreds

      PatientID: None

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: Not specified past “familial pheochromocytoma”

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      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. 445delG

      GroupID/ KindredID: 13

      DiseaseAssertion: VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: Polish

      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: All 3 patients were tallied with a retinal capillary hemangiomas, 2 with cHemangioblastomas, and 1 with RCC. These phenotypes couldn’t be paired as it was not clear with each member.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.A149Pfs*10 (c.445delG)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA432421902 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.445delG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: A149fs (c.445delG)

      MultipleGeneVariants: N/A

    2. 500G>A

      GroupID/ KindredID: 17

      Case: Age unknown, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: This mutation (R167Q (c.500G>A)) was found in Family No. 17 with 1 member affected.

      CasePresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromcytoma)

      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.R167Q (c.500G>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: 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. Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The P71Lfs*61 (c.211_212insT) mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V96).

    2. 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

    1. 1 France c.197_209del p.Val66Glyfs*89

      GroupID: 1

      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.V66Gfs*89 (c.197_209del)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA432536400 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.197del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: V66Gfs*89 (c.197_209del)

      MultipleGeneVariants: N/A

    1. PatientID: 10

      KindredID: Unknown

      Case: M, 40Y0M, Dutch

      DiseaseAssertion: VHL

      FamilyInfo: Unknown - study sampled 15 patients from 5 families

      CasePresentingHPOs: HP:0001737; HP:0000107; HP:0010797; HP:0006880; HP:0005584 (pancreatic cysts, renal cyst, cerebellar hemangioblastoma, spinal hemangioblastoma, renal cell carcinoma)

      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.R167Q (c.500G>A)

      LegacyVariant: p.R238Q

      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: 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

    2. 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. Medical files and histopathology reports of patients who had been operated on before were also reviewed.

      PatientID: IV-23

      KindredID: 1

      Case: M, 35Y0M, Iranian

      DiseaseAssertion: assumed VHL

      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. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Patient had a bilateral PCC at 31Y which was surgically removed at the time. He presently has no abnormal findings.

      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. L101G (20) 

      301 were enrolled in a prospective clinical protocol to evaluate the natural history of vHL-associated pancreatic lesions (NCT00062166). Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study. Individual patient phenotype was not described, but overall of the 60 patients, 57 had RCC, 41 had CNS hemangioblastomas, 28 had retinal hemangioblastoma, 23 had pheochromocytoma. 36/69 patients were female and the mean age was 50.5 years old. Two patients were listed with this mutation, c.301_302delinsGG.

    1. PatientID: None

      KindredID: VHL26

      Case: F, 36Y0M, 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:0002668 (Paraganglioma)

      CaseHPOFreeText: The patient had one malignant abdominal paraganglioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHC/SDHD

      PreviouslyPublished: N/A

      SupplementalData: Table 1 of Supplementary

      Variant: Exon 3 Deletion (c.464-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: The patient had no LOH found in the BAC array CGH data. Somatic VHL variant c.302T>A was found in the tumor tissue.

      MutationType: exon_loss_variant

      CivicName: Exon 3 Deletion

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: VHL25

      Case: M, 31Y0M, 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: Complete Deletion (c.1-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: The patient had no LOH found in the BAC array CGH data. No variants were found in the tumor tissue.

      MutationType: deletion

      CivicName: Deletion

      MultipleGeneVariants: N/A

    3. PatientID: None

      KindredID: VHL1

      Case: M, 22Y0M, 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.S80N (c.239G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Somatic VHL variant c.1-?_642+?del (complete deletion) was found in the tumor tissue.

      MutationType: missense_variant;transversion

      CivicName: S80N (c.239G>A)

      MultipleGeneVariants: N/A

    1. Gene sequencing revealed a heterozygous germline mutation ({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3(VHL):c.464-1G > C) in the splice site in intron 2 of VHL in the DNA from the peripheral blood of the male patient and nine of his family members (male 4, female 5) (Fig. 3a). In total, five of these nine patients from three generations underwent a total of nine surgical resections for CNS-related HGBs, with an average of 1.8 ± 1.3 surgeries (range: 1–4). All resected lesions were located in the cerebellum. Figure 4 shows the genetic investigation used in this study. In the first, second, and third generations, the ages at which the first operation for CNS HGBs was performed were 67, 32.3, and 17 years, respectively. Notably, the age at which the first operation for CNS HGBs was performed was younger in the children (younger generation) than in their parents (older generation). Additionally, only the mother of the male patient with the {"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3(VHL):c.464-1G > C variant was diagnosed with renal cell carcinoma and underwent left nephrectomy.

      PatientID: III-2

      KindredID: 1

      Case: F, Age Unknown, Chinese (East Asian)

      DiseaseAssertion: Asymptomatic

      FamilyInfo: A total of 9 of family members (4 male; 5 female) in a 3 generation family were associated with VHL at the splice mutation: c.464-1G>C. 5 members underwent cerebellar HB lesion resections, including her mother and uncles, and 1 member had RCC. (See Fig 4).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.464-1G>C

      LegacyVariant: N/A

      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. The proband’s son (III.1) inherited his father’s germline VHL large deletion, and not the VHL p. Pro81Ser variant. In addition, the son (III.1) was found to have a hemizygous VHL c.340 + 5 G→C (IVS1 + 5) polymorphic variant, present on the allele inherited from his healthy mother (II.2). The son (III.1) was, therefore, clinically screened and found to have retinal and cerebellar hemangioblastomas as well as pancreatic cysts, typical lesions of VHL demonstrating that VHL cosegregated with, and is therefore caused by, the VHL large deletion and not the p.Pro81Ser variant.

      PatientID: III.1

      KindredID: 3

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient inherited this mutation from his healthy mother (II:2). The patient's father (II:1) was the proband and had two VHL mutations, one of which he passed down to his son (exon 1-3 deletion). The father had hemangioblastomas and pancreatic cysts. The grandfather (I:1) had a P81S mutation but was otherwise healthy. Refer to pedigree in Figure 1-C.

      CohortInfo: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.

      CasePresentingHPOs: HP:0001737, HP:0006880, HP:0009711 (pancreatic cysts, cerebellar hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHD/SDHC

      PreviouslyPublished: May have been previously published in 11106358 and/or 7563486.

      SupplementalData: Yes, File 1 for methods.

      Variant: Exon 1-3 loss

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 1-3 Deletion and Splice Region (c.340+5G>C)

      MultipleGeneVariants: Germline, VHL, c.340+5G>C

    1. 30a7Fc.464T>A3Missensep.Val155Glu24P, muSynchronous

      PatientID: 30

      KindredID: 7

      Case: F, 24Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 2 members of this family, IDs #30 (24Y, F) and #31 (8Y, M) presented with the same variant and pheochromocytoma.

      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 (Pheochromocytoma)

      CaseHPOFreeText: Synchronous multifocal pheochromocytoma. 24Y at VHL diagnosis.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V155E (c.464T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756032, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351756032

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V155E (c.464T>A)

      MultipleGeneVariants: N/A

    1. PatientID: V-6

      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:0010797 (Hemangioblastoma)

      CaseHPOFreeText: CNS hemangioblastoma. 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

    2. PatientID: V-4

      KindredID: 1

      Case: M, 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. GroupID: 3731

      DiseaseAssertion: assumed VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 5 family members recorded with this mutation.

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

      GroupHPOFreeText: 1 patient was recorded with an angioma (hemangioma), 2 with CNS hemangioblastoma, and 4 with pheochromocytomas

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 19464396, 9829911, 10458336, 8956040 (in Zbar 1996 Type 2 3731NCI)

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R167Q (c.713G>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

    2. GroupID: 3315

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

      GroupHPOFreeText: 1/4 members had a retinal angioma (hemangioma), 2 had CNS hemangioblastoma, and 2 had RCC

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Possibly previously published in PMID 9829911

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.S182N (c.545G>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. VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations.

      PatientID: None

      KindredID: 113

      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 113

      CasePresentingHPOs: Unknown

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No presence of phaeochromocytoma in family

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L188Rfs*14 (c.563delT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.L188fs (c.776delT)

      ClinVarID: N/A

      CAID: CA432423679 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.563delT

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: L188fs (c.563delT)

      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: III-5

      KindredID: 1

      Case: F, Age Unknown (deceased), 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 female (III-5) appears to have inherited this disease from her mother and has passed it onto to her daughter thereafter. See Fig. 1 for family pedigree.

      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.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

    2. 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-1

      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-1) appears to have inherited this disease from his father, along with many of his siblings. See Fig. 1 for family pedigree.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: This member had pheochromocytoma which was not further described.

      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

    3. 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-27

      KindredID: 1

      Case: F, 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-27) appears to have inherited this disease from her father. See Fig. 1 for family pedigree.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: This member was examined in St. Johns at the Memorial University of Newfoundland. She had cerebellar hemangioblastoma which were not further described. She also presented with Vitamin-D-Resistant rickets, likely inherited from her father, 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. GroupID: None (14)

      DiseaseAssertion: VHL

      GroupSize: 1

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This family group of 1 individual has clinically confirmed VHL disease presenting with retinal angiomatosis. This individual was found to harbor a c.340+1G>A splice variant (noted in the paper as c.553+1G>A due to Latif reference transcript being used).

      GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal angiomatosis

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+1G>A

      LegacyVariant: c.553+1G>A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223190, https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition; splice_site_variant

      CivicName: Splice Site (c.340+1G>A)

      MultipleGeneVariants: N/A

    2. GroupID: None (20)

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This family group of 2 individuals have clinically confirmed VHL disease. These individuals were found to harbor a c.463+3A>G splice variant (noted in the paper as c.676+3A>G due to Latif reference transcript being used).

      GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal angiomatosis in at least one patient.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.463+3A>G

      LegacyVariant: c.676+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: missense_variant;transition; splice_site_variant

      CivicName: c.463+3A>G

      MultipleGeneVariants: N/A

    1. PatientID: 123

      KindredID: 43

      Case: M, Age 60Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

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

      CaseHPOFreeText: The proband's father (patient 123) presented with a CNS hemangioblastoma at age 27, renal cell carcinoma at age 48, and multiple pancreatic cysts/tumors at age 60.

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

      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: p.W117R (c.349T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753664; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117R (c.349T>A)

      MultipleGeneVariants: N/AcDNAposition:349

    2. A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. An in-frame deletion (c.227_229del, equivalent to c.224_226del) was confirmed in 3 families (#9, #10 and #11). Family #9: A female patient (patient #27) was confirmed for this in-frame deletion in the VHL gene. She was diagnosed with CNS haemangioblastoma at 36Y, renal cell carcinoma at 40Y, and multiple pancreatic cysts or tumours at 40Y. Family #10: A male patient (#28) was diagnosed with CNS hemangioblastoma at 21Y and confirmed to have the mutation. His son (#29) was also confirmed to have the mutation, but was asymptomatic (age unknown). Family #11: A female proband (#30) was diagnosed with CNS hemangioblastoma at 28Y, retinal angioma at 26Y, renal cell carcinoma at 37Y, and multiple pancreatic cysts or tumours at 28Y (mutation confirmed); her son (#31) with a mutation confirmed but no manifestations (asymptomatic) and age unknown. She had four family members who passed away before they could be confirmed with the mutation. Her father (#32) diagnosed with CNS hemangioblastoma at 42Y; Brother 1 (#32) diagnosed with CNS hemangioblastoma at 28Y; Brother 2 (#33) diagnosed with CNS hemangioblastoma at 30Y; and uncle (#34) with retinal angioma diagnosed at 60Y. This cohort was also published in a 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.

    3. A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #58 with 3 affected members who were all genetically confirmed with the mutation. A male proband (patient 155) was diagnosed with retinal angioma at 21Y, renal cell carcinoma at 26Y, and multiple pancreatic cysts/tumors at 26Y. His sister (patient 156) was diagnosed with CNS hemangioblastoma at 21Y and multiple pancreatic cysts/tumors at 27Y. His nephew (son of sister) of unknown age was asymptomatic at the time of analysis. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

    4. PatientID: 25

      KindredID: 7

      Case: M, 58Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband, patient 23, had a brother (patient 24) and father (patient 25) who were both genetically confirmed with the mutation. The brother presented with a CNS hemangioblastoma, renal cell carcinoma, and pancreatic cysts/tumors at age 32. The father presented with renal cell carcinoma and pancreatic cysts/tumors at age 58.

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

      CaseHPOFreeText: The proband's father, patient 25, presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

      CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)

      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.R69Afs*63 (c.204_205insG)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA913189244; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.204_205insG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: R69AFS*63 (c.204_205insG)

      MultipleGeneVariants: N/A

    5. 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

    1. 5 (33)

      GroupID: 2b

      DiseaseAssertion: VHL

      GroupSize: 5

      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: N/A

      GroupHPOFreeText: These 5/15 patients with a VHL gene deletion did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

      GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes - Supplementary Table S1

      Variant: VHL gene deletion

      LegacyVariant: N/A

      GroupProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion

      CivicName: Null (Complete Deletion)

      MultipleGeneVariants: N/A

    1. F5, II.2c.430G>A/c.340+694_711dupVHL p.Gly144Arg/X1 p.Trp159X?1975/13 yM16.2605.9Erythrocytosis—

      PatientID: II.2

      KindredID: F5

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0001901 (Polycythemia)

      CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) at age 13 (DOB: 1975).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G144R (c.430G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 576437, https://www.ncbi.nlm.nih.gov/clinvar/variation/576437/

      CAID: N/A

      gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188287-G-A?dataset=gnomad_r2_1

      VariantEvidence: Variants are heterozygous.

      MutationType: missense_variant;transition

      CivicName: G144R (c.430G>A) and c.340+694_340+711dup

      MultipleGeneVariants: Germline, VHL, c.340+694_340+711dup

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

      PatientID: I.3

      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:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

      CaseHPOFreeText: Presented with CNS hemangioblastoma and pheochromocytoma. Tumors detected at ages 24 and 46.

      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

    3. F5

      PatientID: None (Sister 2)

      KindredID: F5

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+694_340+711dup

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 816686, https://www.ncbi.nlm.nih.gov/clinvar/variation/816686/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: duplication; splice_site_variant

      CivicName: c.340+694_340+711dup

      MultipleGeneVariants: N/A

    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+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

    5. 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

    6. 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)

    7. 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

    1. A 27-year-old man

      PatientID: None

      KindredID: 1

      Case: M, 27Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009713; HP:0000479; HP:0001737 (Spinal hemangioblastoma, renal cysts, pancreatic cysts)

      CaseHPOFreeText: The patient, a 27Y male, presented with severe back pain, paraplegia and urinary retention, and numbness below his waist. Upon investigation, a cystic lesion with enhancing nodules expanding the cervical cord from C2 to C3 and an irregular enhancing mass expanding from T6 to T9 associated with extensive edema. Further investigation found multiple cystic lesions scattered throughout the pancreas and both kidneys. The patient’s neurological symptoms resolved after tumour removal.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: T105P(c.313A>C)

      LegacyVariant: N/A

      ClinVarID: 496055, https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: T105P(c.313A>C)

      MultipleGeneVariants: N/A

    1. five other individuals in the family had succumbed to cerebral hemangioblastomas.

      PatientID: None (5 family members)

      KindredID: 1

      Case: Sex unknown, Age unknown, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Recorded family history of VHL disease, with the 34Y old proband having cerebellar hemangioblastoma, renal cell carcinoma and pancreatic endocrine tumour and a confirmed c.473T>C mutation; 7 other family members had the mutation: The proband’s mother, grandmother, two uncles and three aunts also suffering from the disease. One uncle had succumbed to RCC and five other individuals in the family had succumbed to cerebral hemangioblastomas, although which member is unclear. No mutation was stated.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: 5 members in the extended family of the proband have cerebral HBs.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: unknown

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: N/A

      CivicName: N/A - (L158P (c.473T>C))

      MultipleGeneVariants: N/A

    1. Case 3 involved a male patient first diagnosed with a 6–7 cm left adrenal pheochromocytoma resected at age 51. He was later referred to the NIH where at age 72 surgical debulking was carried out revealing diffuse peritoneal metastases.

      PatientID: 3

      KindredID: 3

      Case: M, 72Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: First diagnosed with a left adrenal pheochromocytoma resected at age 51. He was later referred to the NIH where at age 72 surgical debulking was carried out revealing diffuse peritoneal metastases.

      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: c.340+5G>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

      CAID: N/A

      gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

      VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

      MutationType: splice_site_variant

      CivicName: Splice Region (c.340+5G>C)

      MultipleGeneVariants: N/A

    1. A 12-year-old girl presenting with intermittent epigastric pains and diarrhea was referred to our clinic. Diagnostic workup revealed nonfunctional bilateral adrenal pheochromocytomas as well as a neuroendocrine tumor of the pancreatic head. This is the first report on the combination of a neuroendocrine pancreatic tumor with adrenal pheochromocytoma in a pediatric patient with von Hippel–Lindau (VHL) disease.

      PatientID: 1 (case)

      KindredID: 1

      Case: F, 12Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Family history revealed that her mother had had bilateral partial adrenalectomy for pheochromocytoma during her youth; more recent follow-up investigations of the patient’s mother also revealed cerebral hemangioblastomas and a neuroendocrine tumor of the pancreatic head with liver metastases. She also showed the same mutation upon further follow-up.

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

      CaseHPOFreeText: Patient was affected for 1 year prior diagnosis by intermittent epigastric pains and diarrhea (clinical workup revealed a pancreatic tumor). Patient also showed a bilateral adrenal enlargement (pheochromocytoma - (11 mm right and 17 mm left)). There was no evidence of infiltration of the vena mesenterica superior. The mesentericoportal venous trunk and the large arterial vessels of the epigastrium were dissected from the tumor and preserved.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      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. PatientID: 22

      KindredID: 22

      Case: F, 43Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006880; HP:0005584 (Cerebellar hemangioblastoma, Renal cell carcinoma)

      CaseHPOFreeText: Cerebellum hemangioblastoma and RCC.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.475T>A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Preoperative hemoglobin: 15.2. No postoperative follow-up.

      MutationType: missense_variant;transversion

      CivicName: W88R (c.262T>A)

      MultipleGeneVariants: N/A

    1. 4 AGY29/MPheochromocytoma (Bilateral renal and eyes, pancreatic cysts))Mother, brother (Case 5)VHL{"type":"entrez-nucleotide","attrs":{"text":"NM_000551.4","term_id":"1779521775"}}NM_000551.4:c.202T>Cp.(Ser68Pro)CM073416

      PatientID: 4 AGY

      KindredID: 4

      Case: M, 29Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: The patient's mother was an affected family member described (no mutation or phenotypes detailed). Additionally his brother (case 5) had the same mutation with pheochromocytoma and right ccRCC.

      CasePresentingHPOs: HP:0002666; HP:0001737 (Pheochromocytoma; Pancreatic cysts)

      CaseHPOFreeText: Patient had bilateral renal and eyes pheochromocytoma, with pancreatic cysts

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET, SDHB, SDHD, TMEM127

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S68P (c.202T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA16621912 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.202T>C

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: S68P (c.202T>C)

      MultipleGeneVariants: N/A

    1. ii) renal cyst 17

      PatientID: N/A

      KindredID: 3

      Case: Sex Unknown, 17Y0M, Ethnicity Unknown

      DiseaseAssertion: Renal Cyst

      FamilyInfo: This patient (a relative of patient B3) had two first degree relatives who were positive for the VHL mutation. The first family member (patient B3) had a cerebellar hemangioblastoma at 40 and a pheochromocytoma at 41 years old and the second family member had a hemangioblastoma and retinal angioma at 18 years old

      CasePresentingHPOs: HP:0000107 (renal cyst)

      CaseHPOFreeText: N/A

      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)

      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. 1Deletion

      PatientID: proband 17

      KindredID: 17

      Case: M, 21Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: the patients mother was found at 43Y with RCC and multiple pancreatic cysts or tumors, however she passed before any diagnosis of DNA sample was provided

      CasePresentingHPOs: HP:0009711; HP:0009715 (retinal capillary hemangioma, Papillary cystadenoma of the epididymis)

      CaseHPOFreeText: patient was found with retinal hemangioblastomas and epididymal/ovarian cystadenoma at 21Y

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: exon 1 deletion

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: exon 1 deletion

      MultipleGeneVariants: N/A

    2. 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. 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: 23

      KindredID: C

      Case: Sex Unknown, 9Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: asymptomatic

      FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patient was asymptomatic at the time, likely due to young age

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

      SupplementalData: N/A

      Variant: p.T100Nfs*32 (c.298dupA)

      LegacyVariant: c.1012_1013insA

      CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

      ClinVarID: N/A

      CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

      gnomAD: N/A

      VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

      MutationType: plus_1_frameshift_variant; duplication

      CivicName: T100Nfs*32 (c.298dupA)

      MultipleGeneVariants: N/A

    1. another affected relative [III-A, in the pedigree]

      PatientID: III-A

      KindredID: 1

      Case: M, 45Y0M, EthnicityUnknown

      DiseaseAssertion: VHL

      FamilyInfo: Multiple first- and second-degree relatives affected with similar phenotypes. Of these, he is genetically tested and found to share VHL mutations with his uncle (proband).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Paper asserts that this individual presented with VHL phenotypes but does not specify which.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Information obtained from Figure 1

      Variant: c.340+5G>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

      CAID: N/A

      gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

      VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

      MutationType: splice_site_variant

      CivicName: P86S (c.256C>T) and Splice Region (c.340+5G>C)

      MultipleGeneVariants: Germline, VHL, L158Q (c.473T>A)

    1. VHL, female, 12VHLc278G→A pGly93Asp, VHL diseaseRetinoblastomaMother had pheochromocytoma, VHL follow-up

      PatientID: None

      KindredID: 1

      Case: F, 12Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Mother had pheochromocytoma and positive family history of VHL.

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

      CaseHPOFreeText: Retinoblastoma.

      CaseNotHPOs: HP:0002668 (Paraganglioma)

      CaseNotHPOFreeText: Criteria for exclusion were 1) absence of intra-adrenal tumor, 2) paragangliomas explicitly, 3) extra-adrenal secreting chromaffin tumors, 4) nonsecreting head–neck paragangliomas, 5) no operation, and 6) patients with normal levels of both urinary catecholamines and plasma metanephrines.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table 2

      Variant: p.G93D (c.278G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G93D (c.278G>A)

      MultipleGeneVariants: N/A

    1. 13 (17%) had large deletions,

      PatientID: 80

      KindredID: 80

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030421 (Epididymal neoplasm)

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

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

      Variant: complete deletion

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion

      CivicName: Deletion

      MultipleGeneVariants: N/A

    2. 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

    3. 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

    1. nt 529 Ins.GCC1-150 106Ins. Arg529ins3In-frame ins1

      PatientID: 16

      GroupID/ KindredID: 16

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: other phenotypes unknown.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R108dup (c.322_324dupCGC)

      LegacyVariant: Ins. Arg (c.529insGCC)

      CaseProblemVariantFreeText: AF010238.1: Ins. Arg (c.529insGCC) translates to: NM_000551.3:c.316_317insGCC which automaps to NM_000551.3:c.322_324dupCGC due to the 3’ rule, so the two are both consistent and possible with this mutation

      ClinVarID: N/A

      CAID: CA916832608 https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA916832608

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: duplication

      CivicName: R108dup (c.322_324dupCGC)

      MultipleGeneVariants: N/A

    1.  c.500G > A11 (15%)2a/b45 (21–65)HBr, HBc,HBsc, RCC,pNET, Pheo, Cr, Cp

      PatientID: None

      KindredID: 14

      Case: Sex Unknown, 65Y0M, 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.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. A425M?? ?-- - -c.280 G[Ap.E94Kb

      PatientID:4

      KindredID: A

      Case: M, 25Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0001737, HP:0010797 (pancreatic cyst, hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0030393 (Retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumor)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E94K (c.280G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 135955 https://www.ncbi.nlm.nih.gov/clinvar/variation/135955/

      CAID: N/A

      gnomAD: 0.000004460 https://gnomad.broadinstitute.org/variant/3-10183811-G-A?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_transition

      CivicName: E94K(c.280G>A)

      MultipleGeneVariants: N/A

    2. S 23 27 M ? ? ? - - - - VHL FLD a – BRK1, FANCD2

      PatientID: 23

      KindredID: KS

      Case: M, 27Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0001737 (Hemangioblastoma, Pancreatic cysts)

      CaseHPOFreeText: CNS hemangioblastoma and multi-cystic pancreatic lesions.

      CaseNotHPOs: HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Complete Deletion

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.

      MutationType: deletion

      CivicName: Deletion

      MultipleGeneVariants: N/A

    3. S4 17 20 F - - - ? - ? - c.464 T[G (463 ? 43 A[G) p.V155G a–b interface

      PatientID: 17

      KindredID: S4

      Case: F, 20Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: Retinal angioma and pheochromocytoma.

      CaseNotHPOs: HP:0030393; HP:0010797; HP:0001737; HP:0005584 (Endolymphatic sac tumor, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V155G (c.464T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA16621938, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464T%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant; missense_variant;transversion

      CivicName: V155G (c.464T>G) and c.463+43A>G

      MultipleGeneVariants: Germline, VHL, c.463+43A>G

    1. This patient's brother (3 years younger) was followed with the similar accelerated screening protocol of biannual visits with alternating US and plasma catecholamines from the age of 5. At 11 years, the brother had a normal abdominal US, but, 6 months after, he was found to have plasma norepinephrine at 51,506 pmol/L, a 36-fold increase compared to the preceding year. MRI revealed a 3.5 cm adrenal mass, which at retroperitoneoscopic surgery required total adrenalectomy for excision. Pathology confirmed a 2.9 cm pheochromocytoma without residual tumor at the margins. This patient is followed since with a second version of an accelerated regimen. The second iteration of an accelerated regimen consists of biannual plasma catecholamines and visits with annual US. The brother is currently well after 2 years and a half of surveillance.

      PatientID: N/A (younger son of index case)

      KindredID: 1

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient's mother was the index case in this VHL family, as she was diagnosed with bilateral pheochromocytoma at age 23 and underwent bilateral adrenalectomy. Genetic screening of the mother revealed the VHL variant, which prompted screening of family members. DNA sequencing from blood of consenting family members confirmed the presence of the VHL variant in seven family members (three generations from the maternal side) (see figure 1 for familial pedigree). This included the mother (index case), the patient, his brother, maternal grandmother, uncle and two cousins. The brother, who was 3 years older, was asymptomatic until age 7, where an abdominal ultrasound revealed a left adrenal mass. A total adrenalectomy was performed and at age 1 another mouse was found in the right adrenal gland, which was also removed. 6 years later he was asymptomatic. The uncle developed hemangioblastoma, multiple bilateral renal cell carcinomas, bilateral pheochromocytomas, and succumbed to his disease at age 45. The uncle's two daughters both had the mutation. One of which was found to have pheochromocytoma at age 15 due to routine screening. The other 8 year old daughter has not had any manifestations. No phenotype was noted for the grandmother.

      CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

      CaseHPOFreeText: Patient presented with an adrenal mass at 11Y0M, which required total adrenalectomy and remains well 2.5 years later.

      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, https://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; tranversion

      CivicName: V170G (c.509T>G)

      MultipleGeneVariants: N/A

    1. Further family evaluation revealed clinical and biochemical evidence of (bilateral) pheochromocytoma in two siblings 19 and age 23.

      PatientID: N/A (sibling 1)

      KindredID: 1

      Case: Sex Unknown, 23Y0M, Ethnicity Unknown

      DiseaseAssertion: pheochromocytoma

      FamilyInfo: Her father had bilateral pheochromocytoma at the age of 13 and her grandfather had died of an unknown renal disease at the age of 50. They were both however not tested for any variants. There were no reports of hereditary cutaneous or uterine leiomyomas, renal cell cancer, neuroendocrine tumors or hemangioblastomas of the CNS/retina. Family evaluation revealed clinical and biochemical evidence of (bilateral) pheochromocytoma in two siblings 17 and age 19. These members also had the VHL mutation, while 2 unaffected family members were negative.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: clinical and biochemical evidence showed bilateral pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: FH/RET/MAX/NF1/SDHB/SDHC/SDHD/TMEM127

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114G (c.342T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432421783 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.342T%3EC

      gnomAD: N/A

      VariantEvidence: The FH variant is reported in 9/116704 alleles in the ExAC database. The VHL variant was no reported, however, an T>A transition at the same nucleotide position has been reported once in 1/121408 alleles (ExAC). Researchers suspect synonymous mutation has effects on transcript splicing (2 nucleotides into exon 2).

      MutationType: synonymous_variant

      CivicName: G114G (c.342T>C)

      MultipleGeneVariants: N/A

    1. Affected members of the third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange.

      PatientID: CII2

      KindredID: C

      Case: M, 63Y0M, Serbian

      DiseaseAssertion: VHL

      FamilyInfo: Families were selected based on their clinical data and family history. Patient’s son (CIII1) retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma, but was not genetically tested. The patient’s brother also had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma, but was not genetically tested. Patient’s grandson (CIV2) was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. He possessed the same mutation as the patient. The grandson’s children aged 12Y0M (CV2) and 15Y0M (CV1) are carriers of the same genetic mutation, but are both currently asymptomatic. See pedigree in figure 1.

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

      CaseHPOFreeText: The patient had the first symptoms of retinal hemangioblastoma at 60Y0M and deceased due to renal cell carcinoma in both kidneys at 63Y0M.

      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. third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange

      PatientID: CV1

      KindredID: C

      Case: M, 15Y0M, Serbian

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Families were selected based on their clinical data and family history. Patient and his brother (CV2) are both currently asymptomatic, but possess the same variant as their father (CIV2), who was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. Patient’s grandfather, great grandfather and great uncle (CIII1; CII1, CII2) had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma. Out of the three of them, only the great grandfather had genetic testing performed and was found to have the same mutation as the patient. See pedigree in figure 1.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      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

    3. 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. frameshift mutations (4/16)

      PatientID: 12

      KindredID: 12

      Case: 32Y0M, Sex Unknown, Argentinian

      DiseaseAssertion: VHL

      FamilyInfo: Family history unremarkable; Patient was confirmed to have a de novo mutation.

      CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0030424 (hemangioblastoma; retinal capillary hemangioma; renal cyst; epididymal cyst)

      CaseHPOFreeText: Aged 32Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. Retinal hemangioblastomas and CNS hemangioblastomas diagnosed at 32Y, renal cysts were also diagnosed at 32Y, while epididymal cysts were diagnosed first at 23Y (See Table 1 & 2).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2497423672 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497423672

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift_variant

      CivicName: V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

      MultipleGeneVariants: N/A

    1. A deletion of exon 3 in the VHL gene was found in this family.

      PatientID: III-6

      KindredID: Family A

      Case: M, 31Y0M, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. His aunts II-2 and II-3 both had confirmed VHL and CNS hemangioblastoma. His dad (II-3) has confirmed VHL gene and pancreatic and renal cysts. His cousins (2 boys 1 girl: III-3; III-5; III-3) were all found with the confirmed VHL gene mutation; III-3 and III-5 with retinal hemangioblastoma and CNS/spinal hemangioblastomas and III-4 with pancreatic and ovarian cysts. Patient’s son and nephew IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

      CasePresentingHPOs: HP:0005584; HP:001079 (renal cell carcinoma, hemangioblastoma)

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Deletion of exon 3 (c.464-?_642+?del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: exon_loss_variant

      CivicName: Exon 3 deletion

      MultipleGeneVariants: N/A

    1. #12PCC(34)10c.340+866C>Ars5366316850.02NANANANANAVUS

      PatientID: 12

      KindredID: 12

      Case: Sex Unknown, 44Y0M, Ethnicity Unknown

      DiseaseAssertion: Pheochromocytoma

      FamilyInfo: N/A - not stated

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: A pheochromocytoma (PCC) diagnosed first at 34Y was found, with follow up of a 10 year duration.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes

      Variant: c.340+866C>A

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA70046858 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B866C>A

      gnomAD: N/A

      VariantEvidence: Paper described this allele frequent as 0.02%, although not described in the gnomAD database.

      MutationType: splice_site_variant; intron_variant

      CivicName: Splice Site (c.340+866C>A)

      MultipleGeneVariants: N/A

    1. We studied six patients with VHL disease and their relatives. Loss of heterozygosity (LOH) was determined by five flanking microsatellite polymorphic markers in the VHL locus.

      PatientID: 16

      KindredID: F01

      Case: F, Age Unknown, Taiwanese

      DiseaseAssertion: VHL

      FamilyInfo: A total of 10 members of this family (F01) had a complete deletion of the VHL gene. Four of these patients (16, 18, 21, 33) presented with clinical features of VHL.

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: Brain hemangioblastoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19288063

      SupplementalData: Figure 1

      Variant: Complete Deletion

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Deletion of 142.9kb resulted in deletion of the VHL gene.

      MutationType: deletion

      CivicName: Deletion

      MultipleGeneVariants: N/A

    1. a case

      PatientID: None

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient’s aunt died of a cerebellar tumor of unknown pathology at 30Y. The patient’s father presented with giant pheochromocytoma at age 46, meningothelial meningioma and capillary hemangioblastoma at age 66, and died from cerebral infarctions and RCC at age 69.

      CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L158V(c.472C>G)

      LegacyVariant: p.L158V(c.685C>G)

      ClinVarID: 567944, https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: L158V(c.472C>G)

      MultipleGeneVariants: N/A

    2. a case

      PatientID: None

      KindredID: 1

      Case: M, 66Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient’s elder sister died of a cerebellar tumor of unknown pathology at 30Y. As well, the patient’s son presented with cerebellar hemangioblastoma and was diagnosed with VHL disease.

      CasePresentingHPOs: HP:0002666; HP:0006880; HP:0100009; HP:0005584 (Pheochromocytoma, cerebellar hemangioblastoma, intracranial meningioma, renal cell carcinoma)

      CaseHPOFreeText: The 66Y male patient presented with mild dementia, and was found to have multiple tumours in the cerebellum; the tumours were resected, and histological examination determined that the tumours included meningothelial meningioma and a capillary hemangioblastoma. The patient was also found to have renal cell carcinoma, and underwent nephrectomy. The patient had also previously undergone resection for a giant pheochromocytoma associated with malignant hypertension 20 years prior at 46Y. The patient died of multiple cerebral infarctions and RCC three years after the surgery to remove the cerebellar tumours.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L158V(c.472C>G)

      LegacyVariant: p.L158V(c.685C>G)

      ClinVarID: 567944, https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: L158V(c.472C>G)

      MultipleGeneVariants: N/A

    1. 26m417.6n19.4↑553 G/A–6.7

      PatientID: 26

      KindredID: 26

      Case: M, 41Y0M, 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.G114S (c.340G>A)

      LegacyVariant: c.553G>A

      CaseProblemVariantFreeText: 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

    1. No abstract available

      PatientID: IV-3

      KindredID: 1

      Case: M, 77Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient’s mother and two brothers had died with cerebellar hemangioblastoma, although genetic testing was not performed. One of the patient’s four children, a 46Y male, also presented with a small renal tumour, renal cysts, and pancreatic cysts; he was found to carry the same mutation the patient carried. One of the patient’s grandsons, 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:0006880; HP:0001737; HP:0006770; HP:0006748; HP:0000479 (Cerebellar hemangioblastoma, pancreatic serous cystadenoma, clear cell renal cell carcinoma, adrenal pheochromocytoma, retinal lesions)

      CaseHPOFreeText: The patient was originally diagnosed with metastatic bilateral clear cell renal cell carcinoma at 68Y and underwent chemotherapy for three months. The metastases were later reinterpreted to be a cystic hemangioblastoma and a benign serous cystadenoma. The patient was also found to have a non-secreting adrenal pheochromocytoma at 73Y and a clear cell renal cell carcinoma metastasis in the thyroid at 74Y. The patient had also previously presented with retinal lesions, although detailed records were unavailable.

      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

    2. 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. PMID: 29813026

      PatientID: 3

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A - Not specified

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: VHL syndromic HB

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E94K (c.280G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 135955 https://www.ncbi.nlm.nih.gov/clinvar/variation/135955/

      CAID: N/A

      gnomAD: 0.000004460 https://gnomad.broadinstitute.org/variant/3-10183811-G-A?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: E94K (c.280G>A)

      MultipleGeneVariants: N/A

    1. V#3exon 3c.525C > Ap.Y175XPancreatic cysts and renal carcinoma

      PatientID: 3

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes

      Variant: p.Y175* (c.525C>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 1298905, https://www.ncbi.nlm.nih.gov/clinvar/variation/1298905/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Y175* (c.525C>A)

      MultipleGeneVariants: N/A

    1. 12 missenses

      GroupID/ KindredID: 14

      DiseaseAssertion: assumed VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: Chinese

      GroupAgeRange: N/A

      GroupInfo: With a family history, 5 family members were recorded in this group with the given mutation.

      GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma; pancreatic lesion)

      GroupHPOFreeText: 4 members had CNS hemangioblastomas, 1 had a retinal angiomas, 3 had RCC, 1 had a pancreatic abnormality

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: No family members appeared to have the above manifestation.

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.S111N (c.545G>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. 5 F/11 PCC VHL 3 c.482G>A (p.Arg161Gln) Post-NGS Targeted NGS P Bilateral adrenal 2.0 Benign Yes Symptomatic Noradrenergic

      PatientID: 5

      KindredID: 5

      Case: F, 11Y0M, Korean

      DiseaseAssertion: Adrenal Pheochromocytoma

      FamilyInfo: No information provided.

      CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

      CaseHPOFreeText: The patient presented with adrenal pheochromocytoma (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.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: 16 (tumour 28)

      KindredID: 5

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      PatientID: (proband)

      KindredID: 2

      Case: F, 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 mother

      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.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. 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

    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. We report two young male twins with simultaneously manifesting haemangioblastomas of the right cerebellar hemisphere. In one, the neoplasm was associated with medullary and spinal cord solid tumours; in the other, with a nasopharyngeal bleeding fibroangioma, an association not described previously.

      PatientID: III-2

      KindredID: 1

      Case: M, 16Y0M, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo:  2 young male twins were examined with the VHL gene mutation with simultaneously manifesting hemangioblastomas of the right cerebellar hemisphere. Both parents were examined with no VHL mutation, detecting a de novo mutation in the twins. A third sibling, two years older, presented with a cafè au lait skin spot. Grand mother had bilateral high myopia and glaucoma. The medical history of the pedigree shows that member (I-1) had severe hypertension and died at 60 from a stroke, member (I-2) died at 40 from ovarian carcinoma, and member (I-3) died at 54 from clinically diagnosed intracerebral haemorrhage.

      CasePresentingHPOs: HP:0006880; HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

      CaseHPOFreeText: in 1994 patient came complaining of blurred vision thought to be due to his myopia. MRI showed a large cyst and a 4.3 cm mural ovoid nodule in the right cerebellar hemisphere. Another small mural nodule was present in the infero-posterolateral portion of the right cerebellar hemisphere. CT disclosed a round homogeneous, hyperintense nodule at T1 in the spinal cord. Raised intracranial pressure due to the compression of aqueduct from the tumour accounted for hydrocephalus and enlarged lateral and 3rd ventricles.

      CaseNotHPOs: HP:0001901 (polycythemia)

      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: N/A

      MultipleGeneVariants: N/A

    1. Although two of her three children have inherited the mutation, they have had no disease manifestations.

      PatientID: None (Child 1)

      KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Awaiting testing of the proband’s eight siblings to determine whether or not this is a de novo mutation causing VHL disease. Two of three of the proband’s children have inherited the mutation, they have had no disease manifestations.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G144R (c.430G>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 576437, https://www.ncbi.nlm.nih.gov/clinvar/variation/576437/

      CAID: N/A

      gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188287-G-A?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G144R (c.430G>A)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: The proband was part of a cohort of apparently sporadic cases of pheochromocytoma/ paraganglioma, implying this individual had no family history of VHL disease or pheochromocytoma.

      CasePresentingHPOs: HP:0006748 (Adrenal Pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0002668 (Paraganglioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET, SDHB, SDHC, and SDHD

      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: 3

      KindredID: A (III-11)

      Case: M, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient's mother (II:7) carried the VHL mutation and presented with hemangioblastoma, renal cell carcinoma, pheochromocytoma, and renal cysts. The patient had one brother (III:12) who had the mutation and presented with renal cell carcinoma, one asymptomatic sister (III:10) who did not undergo genetic testing and a sister (III:13) who had the mutation and renal cell carcinoma, retinal angioma, and hemangioblastoma. On the mother's side of the family there was extensive history of VHL disease. Refer to Figure 1 for family pedigree and information regarding extended family members.

      CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

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

      CaseHPOFreeText: Diagnosed with renal cell carcinoma and retinal angioma at age 26. Underwent radical nephrectomy of both the right and left side. There was a complication, interstitial cellular rejection and retroperitoneal abscess. The patient had five renal cell carcinomas and five renal cysts. The patient had a satellite lesion.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      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. 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

    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

    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. 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. 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. 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

    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. 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

    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

    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. 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