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    1. Patient II‐1 was admitted to the Department of Urinary Surgery and Neurosurgery in October 2007 and again in December 2015. In the first hospitalization, a serendipitous left kidney mass was found, but no symptoms. Abdominal CT revealed a solid cystic mass on the inside of the left kidney with irregular enhancement (Figure ​(Figure2b),2b), indicating a radiological diagnosis of RCCC. A laparoscopic radical nephrectomy was performed, and pathology confirmed the diagnosis of clear cell carcinoma. In the second hospitalization, the patient was admitted with complaints of headache and dizziness for 2 months. A brain MRI showed a right CH (Figure ​(Figure2c).2c). Tumor resection was performed through a posterior approach, and pathology confirmed the diagnosis of hemangioblastoma. In the most recent follow‐up, his symptoms had disappeared, and radiological imaging revealed no recurrence in either the brain or abdomen.

      PatientID: II-1

      KindredID: 1

      Case: M, 45Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Both of the patient’s brothers (Patient II-3 and II-4), the patient’s sister (II-5), and the patient’s nephew (III-3) were clinically diagnosed with VHL disease. Patient II-4 presented with RCCC at age 53, and carried the mutation NM_000551.3:c.269A>T. Patient III-3 presented with CH and carried the same mutation. The patient’s other brother (Patient II‐3) and sister (Patient II‐5) were deceased and had an undetermined mutation. Patient II-3 died of an advanced RCCC, and Patient II‐5 died of a ruptured CH. The patient’s parents (Patient I-1 and I-2) were also deceased from other causes. The patient’s grand-nephew (Patient IV‐1) was healthy and did not carry the mutation.

      CasePresentingHPOs: HP:0006770; HP:0006880 (Renal clear cell carcinoma, cerebellar hemangioblastoma)

      CaseHPOFreeText: The 45Y male patient was diagnosed with left RCCC at 33Y, but had no symptoms. The patient presented with complaints of headache and dizziness at age 41Y, and was diagnosed with a right cerebellar hemangioblastoma. In the most recent follow‐up, his symptoms had disappeared, and radiological imaging of the brain and abdomen revealed no recurrence.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient.

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

      LegacyVariant: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: N90I(c.269A>T)

      MultipleGeneVariants: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient

    2. The proband (Patient III‐1) was admitted into our ward in October 2015 with a complaint of an occipital headache for 1 month. He was conscious, and a physical examination did not reveal ataxia. Tests for cranial nerve function, limb sensation and motor function were unremarkable. Contrast‐enhanced brain magnetic resonance imaging (MRI) revealed a solid‐cystic mass in the vermis cerebelli and left cerebellar hemisphere (Figure ​(Figure2a),2a), indicating a radiological diagnosis of CH. Cerebellar tumor resection was performed through a sub‐occipital craniotomy under general anesthesia, and the tumor was completely removed. The tumor, which was 30 mm in diameter, was pink and soft and composed of dilated veins and dense blood capillaries. A postoperative pathological analysis of the tumor indicated a hemangioblastoma. The patient completed outpatient follow‐up in October 2018. The occipital headache had disappeared, brain MRI showed no recurrence, and abdominal computerized tomography (CT) revealed no neoplasms.

      PatientID: III-3

      KindredID: 1

      Case: M, 25Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Both of the patient’s uncles (Patient II-1 and II-4) were clinically diagnosed with VHL disease, and carried the mutation NM_000551.3:c.269A>T. Patient II-1 presented with RCCC at age 33 and cerebral hemangioblastoma at age 41. Patient II-4 presented with RCCC at age 53. The patient’s deceased father (Patient II‐3) and deceased aunt (Patient II‐5) were also clinically diagnosed with VHL disease, but the mutation was undetermined before death. His father died of advanced RCCC, and his aunt (Patient II‐5) died of a ruptured CH. The patient’s grandparents (Patient I-1 and I-2) were also deceased from other causes. The patient’s son (Patient IV‐1), wife (Patient III‐2), and mother (Patient II‐2) were healthy and did not carry the mutation. Their annual physical examination did not reveal a hemangioblastoma, kidney mass or abdominal cyst.

      CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

      CaseHPOFreeText: The 25Y male patient presented with occipital headache at 21Y. Upon initial examination, the patient was diagnosed with cerebellar hemangioblastoma and the tumour was resected. The patient completed outpatient follow‐up three years later. The occipital headache had disappeared, brain MRI showed no recurrence, and abdominal CT revealed no neoplasms.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: N90I(c.269A>T)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 45

      Case: M, 13Y0M, 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:0006880; HP:0006770; HP:0000107; HP:0002666; HP:0010797; HP:0030424 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Renal cyst, Pheochromocytoma, Hemangioblastoma, Epididymal cyst)

      CaseHPOFreeText: Epididymal cyst was noted as “eH” instead of “eC” in Table 2. Given that “eH” was not explained in the footnotes of the Table as were all other phenotypes; “eH” was taken to be a typo intended to be “eC”.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 14722919

      SupplementalData: N/A

      Variant: Exon 1-2 Deletion (c.1-?_463+?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 1-2 Deletion

      MultipleGeneVariants: N/A

    2. PatientID: None

      KindredID: 93

      Case: M, 31Y0M, Spanish

      DiseaseAssertion: VHL

      FamilyInfo: Positive for familial antecedents. Family history of renal cysts and clear cell renal cell carcinoma.

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

      CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Exon 3 Deletion (c.464-?_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 3 Deletion

      MultipleGeneVariants: N/A

    1. GroupID: 11

      DiseaseAssertion: assumed VHL

      GroupSize: 9

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 9 of the 573 patients discussed in this paper were found to the mutation belonging to 3 families, all with this mutation

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

      GroupHPOFreeText: 7 patients had retinal angiomas diagnosed at a mean age of 23Y, and 3 patients had cerebellar hemangioblastomas diagnosed at a mean age of 29Y. 5 patients had RCCs with a mean age of diagnosis of 43Y.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.Q73* (c.217C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Q73* (c.217C>T)

      MultipleGeneVariants: N/A

    2. GroupID: 22

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 3 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family. 

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

      GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at the age of 15Y, 1 had cerebellar hemangioblastomas diagnosed at 20Y, and 1 member had RCC diagnosed at 38Y.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.H125Qfs*7 (c.374dupA)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2499307153 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307153

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: duplication

      CivicName: H125fs (c.374insA) 

      MultipleGeneVariants: N/A

    3. GroupID: 5

      DiseaseAssertion: assumed VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 5 of the 573 patients discussed in this paper were found to the mutation belonging to 1 family. This mutation (c.176delC) was found in 1 VHL family with 5 patients.

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

      GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 22Y, 4 patients had cerebellar hemangioblastomas diagnosed at a mean age of 24Y, and 2 patients had RCCs with a mean age of diagnosis of 60Y.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.P59Rfs*8 (c.176delC)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA432536374 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.176delC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: P59fs (c.176delC)

      MultipleGeneVariants: N/A

    4. GroupID: 7

      DiseaseAssertion: assumed VHL

      GroupSize: 7

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 7 of the 573 patients discussed in this paper were found to the mutation belonging to 1 family. This mutation (c.194delC) was found in 1 VHL family with 7 patients.

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

      GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 18Y, 2 patients had cerebellar hemangioblastomas diagnosed at a mean age of 33Y, and 2 patients had RCCs with a mean age of diagnosis of 30Y and one single patient had pheos diagnosed at age 20Y.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.S65Wfs*2 (c.194delC)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA432536395 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: S65FS (c.194delC)

      MultipleGeneVariants: N/A

    5. GroupID: 50

      DiseaseAssertion: assumed VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 5 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family

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

      GroupHPOFreeText: 4 patients had retinal angiomas diagnosed at a mean age of 27Y, and 3 had cerebellar hemangioblastomas diagnosed at a mean age of 32Y

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.R82_V84del (c.243_251delGCGCGTCGT)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658820713 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.243_251del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: R82_V84del (c.243_251del)

      MultipleGeneVariants: N/A

    6. GroupID: 36

      DiseaseAssertion: assumed VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 4 of the 573 patients discussed in this paper were found to have the following mutation belonging to 3 families altogether.

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

      GroupHPOFreeText: all 4 patients had retinal angiomas diagnosed at a mean age of 30Y and cerebellar hemangioblastomas diagnosed with a mean age of 25Y, and 2 had RCC diagnosed at a mean age of 29Y

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.Y185* (c.555C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223233 https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Y185* (c.555C>G)

      MultipleGeneVariants: N/A

    7. GroupID: 4

      Case: 24Y0M, 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.166dupG) was found in 1 VHL family with a single patient.

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

      CaseHPOFreeText: patient had cerebellar hemangioblastoma at 15Y and retinal capillary hemangioma at 24Y

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.A56Gfs*76 (c.166dupG)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA645524645 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.166dupG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: duplication

      CivicName: A56fs (c.166dup)

      MultipleGeneVariants: N/A

    8. GroupID: 39

      Case: 45Y0M, Sex Unknown, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

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

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

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

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

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

      LegacyVariant: N/A

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift_variant

      CivicName: K196fs (c.584_585delAG)

      MultipleGeneVariants: N/A

    9. GroupID: 15

      Case: 23Y0M, Sex Unknown, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

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

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

      CaseHPOFreeText: patient had retinal angiomas at 21Y and cerebellar hemangioblastomas diagnosed at 23Y

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.F91* (c.272_273delinsAA)

      CaseProblemVariantFreeText: c.272T>A and c.273C>A results in c.272_273delinsAA

      LegacyVariant: N/A

      ClinVarID: CA2499307077 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307077

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: delins; stop_gained

      CivicName: F91* (c.272_273delinsAA)

      MultipleGeneVariants: N/A

    10. GroupID: 6

      Case: 31Y0M, 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.182_185delCCGT) was found in 1 VHL family with a single patient.

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

      CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 31Y and cerebellar hemangioblastoma diagnosed at 30Y

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.P61Rfs*5 (c.182_185delCCGT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA658820712 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.182_185del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: P61FS (c.182_185delCCGT)

      MultipleGeneVariants: N/A

    11. GroupID: 53

      DiseaseAssertion: assumed VHL

      GroupSize: 8

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 8 of the 573 patients discussed in this paper were found to have identical variants. This mutation (S65W (c.194C>G)) was found in 1 VHL family with 8 patients.

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

      GroupHPOFreeText: 6 had retinal hemangioblastoma, 5 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. Mean ages for each diagnosis follows: 32 (RH), 39 (CHB), 56 (RCC - with one patient)

      GroupNotHPOs: HP:0002666 (pheochromcytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.S65W (c.194C>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S65W (c.194C>G)

      MultipleGeneVariants: N/A

    12. GroupID: 42

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 3 of the 573 patients discussed in this paper were found to have identical variants. This mutation was found in 1 VHL family with 3 patients.

      GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma, cerebellar hemangioblastoma, pheochromocytoma)

      GroupHPOFreeText: 2 had retinal hemangioblastoma at a mean age of 16Y, one had cerebellar hemangioblastoma at 16Y, and 1 had pheochromcytoma at 14Y.

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      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

    13. GroupID: 42

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 3 of the 573 patients discussed in this paper were found to have identical variants. This mutation was found in 1 VHL family with 3 patients.

      GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma, cerebellar hemangioblastoma, pheochromocytoma)

      GroupHPOFreeText: 2 had retinal hemangioblastoma at a mean age of 16Y, one had cerebellar hemangioblastoma at 16Y, and 1 had pheochromcytoma at 14Y.

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      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

    Tags

    Annotators

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    1. A→G @ 8678 K→E @159

      PatientID: A (Tumor 2)

      KindredID: 1

      Case: F, 57Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: This kindred with a VHL germline deletion was studied. Apparently inherited from her father and paternal grandmother as they were affected, and passed to daughter but no phenotypic data was provided for these familials. Her sister and nephew also presented with hemangioblastomas and this germline deletion, and further somatic details were studied.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: 2 cerebellar HB surgically resected at 57Y and found with somatic mutations in both tumors

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: no VHL-associated visceral malignancies in the patient

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.K159E (c.475A>G)

      LegacyVariant: c.8678 (p.Lys159Glu)

      CaseProblemVariantFreeText: A somatic mutation in exon 3 (nt: c.8678 (p.Lys159Glu)) via Latif et al.’s (1993) old transcript) was used.

      ClinVarID: 825149 https://www.ncbi.nlm.nih.gov/clinvar/variation/825149/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: unspecified germline deletion as demonstrated by FISH analysis. “Second-hit” tumorigenesis displayed due to somatic mutation found, which was not predicted by the specific germline deletion nor by the overall genetic composition of the patient. Both of this patient’s cerebellar tumors had somatic mutations.

      MutationType: missense_variant; transition

      CivicName: Deletion

      MultipleGeneVariants: Germline, VHL, deletion; Somatic, VHL, c.903_904insT (p.*151)

    1. PMID: 21528239

      GroupID/ KindredID: B

      DiseaseAssertion: assumed VHL

      GroupSize: 3

      GroupNumberMales: 1

      GroupNumberFemales: 2

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 3 members: mother (I:1) and her two children, II:1 (M) and II:2 (F) - Each proved to hold the mutation. II:2 was a predicted asymptomatic carrier. The mother (proband) was considered to carry a new mutation.

      GroupPresentingHPOs: HP:0005584; HP:0006880 (renal cell carcinoma; cerebellar hemangioblastoma)

      GroupHPOFreeText: The mother (I:1) had RCC and a cerebellar hemangioblastoma. Her son II:1 had a cerebellar hemangioblastoma.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: The daughter (II:2) is devoid of know manifestations

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N174KFS*29 (c.519insAA)

      LegacyVariant: p.174FS (c.732insAA)

      CaseProblemVariantFreeText: c.519insAA corrects to NM_000551.3:c.520_521dupAA

      ClinVarID: N/A

      CAID: CA2573051315 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051315

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_2_frameshift_variant; duplication

      CivicName: N174FS*29 (c.519insAA)

      MultipleGeneVariants: N/A

    2. PMID: 21528239

      GroupID/ KindredID: A

      DiseaseAssertion: assumed VHL

      GroupSize: 8

      GroupNumberMales: 2

      GroupNumberFemales: 6

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: The kindred comprised of 21 individuals over 4 generations. The following members have a confirmed mutation: I:1 (F, deceased), II:2 (F, deceased), III:2 (F, deceased), III:4 (M), III:6 (F), IV:4 (F), IV:6 (M), IV:7 (F, is predicted to be affected). The 3 deceased members had died from VHL related tumors. Another 3 were suffering from VHL, another developed RCC an cHB, and 1 was a VHL carrier. All 8 members had this mutation

      GroupPresentingHPOs: HP:0005584; HP:0006880; HP:0009711; HP:0030421 (renal cell carcinoma; cerebellar hemangioblastoma; retinal capillary hemangioma; epidymidal tumor)

      GroupHPOFreeText: 5 members had RCC, 5 had multiple cerebellar hemangioblastomas, 2 had retinal capillary hemangioma and 1 had an epidymidal tumor.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: None of the eight VHL carriers of the first kindred had developed pheochromocytoma, and this kindred clearly presents VHL disease type 1

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7700111

      SupplementalData: N/A

      Variant: p.S183Cfs*19 (c.548delC)

      LegacyVariant: p.183 (c.761delC)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795184 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: S183fs (c.548delC)

      MultipleGeneVariants: N/A

    3. PMID: 21528239

      GroupID/ KindredID: A

      DiseaseAssertion: assumed VHL

      GroupSize: 8

      GroupNumberMales: 2

      GroupNumberFemales: 6

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: The kindred comprised of 21 individuals over 4 generations. The following members have a confirmed mutation: I:1 (F, deceased), II:2 (F, deceased), III:2 (F, deceased), III:4 (M), III:6 (F), IV:4 (F), IV:6 (M), IV:7 (F, is predicted to be affected). The 3 deceased members had died from VHL related tumors. Another 3 were suffering from VHL, another developed RCC an cHB, and 1 was a VHL carrier. All 8 members had this mutation

      GroupPresentingHPOs: HP:0005584; HP:0006880; HP:0009711; HP:0030421 (renal cell carcinoma; cerebellar hemangioblastoma; retinal capillary hemangioma; epidymidal tumor)

      GroupHPOFreeText: 5 members had RCC, 5 had multiple cerebellar hemangioblastomas, 2 had retinal capillary hemangioma and 1 had an epidymidal tumor.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: None of the eight VHL carriers of the first kindred had developed pheochromocytoma, and this kindred clearly presents VHL disease type 1

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7700111

      SupplementalData: N/A

      Variant: p.S183Cfs*19 (c.548delC)

      LegacyVariant: p.183 (c.761delC)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795184 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: S183fs (c.548delC)

      MultipleGeneVariants: N/A

    1. Complete deletion

      GroupID/ KindredID: 28

      PatientID: IV

      Case: 62Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another was diagnosed with a single cerebellar HAB at 24Y, and a final relative (40Y), was diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient was diagnosed with a single HAB at 62Y.

      GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    2. Complete deletion

      GroupID/ KindredID: 28

      PatientID: III

      Case: 40Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another was diagnosed with a single cerebellar HAB at 24Y, and a final relative (62Y), diagnosed with a single HAB.

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

      CaseHPOFreeText: Patient was diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    3. Complete deletion

      GroupID/ KindredID: 28

      PatientID: I

      Case: 27Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 24Y) diagnosed with a single cerebellar HAB, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

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

      CaseHPOFreeText: Patient was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    4. Complete deletion

      GroupID/ KindredID: 28

      PatientID: II

      Case: 24Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

      GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    5. Complete deletion

      GroupID/ KindredID: 28

      PatientID: II

      Case: 24Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

      GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    1. 11Cerebellum505 T/CY98HMissenseNINegative

      PatientID: 11

      KindredID: 9

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Two other members of this family (patients 13 and 17) had the same VHL gene mutation. Patient 13 presented with cerebellar hemangioblastoma. Patient 17 presented with hemangioblastoma of the spinal cord and hemangioblastoma of the medulla oblongata.

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.Y98H (c.505T>C)

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    2. 10Cerebellum479 T/CL89PMissenseNINegative

      PatientID: 10

      KindredID: 4

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

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

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    3. 10Cerebellum479 T/CL89PMissenseNINegative

      PatientID: 10

      KindredID: 4

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

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

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    1. PatientID: 2

      KindredID: P1

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: One other patient belonging to the same family (P1) had this mutation. They had 1 HB and 1 pheochromocytoma

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: two cerebellar hemangioblastomas were detected in this patient

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.R167W (c.712C>T)

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

      CAID: N/A

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

      VariantEvidence: Tested the tumors for somatic mutations but did not detect any

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 1

      KindredID: 26

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: one cerebellar hemangioblastoma was detected in this patient

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V170F (c.508G>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.V170F (c.721G>T)

      ClinVarID: N/A

      CAID: CA351756193 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.508G%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V170F (c.508G>T)

      MultipleGeneVariants: VHL, Somatic, c.576del13 (p.Asn193Met*9)

    1. B6 CHB 22 c.698G → A, C162Y No 2 y 7 m Nil No testing 

      Patient ID: B6

      KindredID: 6

      Case: F, 22Y0M, Ethnicity Unknown

      DiseaseAssertion: cerebellar hemangioblastoma

      FamilyInfo: No testing in family history

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: no other clinical features were found after the cerebellar hemangioblastoma during 2 years and 7 month follow-up

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.C162Y (c.698G>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

    2. B5 CHB 39 c.811C → T, R200W No 6 y 3 m Nil 2 FDRs mutation positive

      PatientID: B5

      KindredID: 5

      Case: Sex Unknown, 39Y0M, Ethnicity Unknown

      DiseaseAssertion: cerebellar hemangioblastoma

      FamilyInfo: Two first degree relatives were found to have the same mutation in the VHL gene, both had no features of VHL disease at 28 and 38 years old

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: no other clinical features were found after the cerebellar hemangioblastoma during 6 years and 3 month follow-up

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.R200W (c.811C>T)

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R200W(c.598C>T)

      MultipleGeneVariants: N/A

    1. In patient II/1 (Figure 1) the 8684 C->T substitution causing the nonsense R161X mutation in the putative protein was found

      PatientID: II/1

      KindredID: 1

      Case: F, 33Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: A patient was found to have a mutation in the VHL gene (R161* (c.481C>T)), this patients parents were tested for the same mutation in VHL, but testing revealed no VHL gene mutation. Pedigree: see Figure 1.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: developed cerebellar hemangioblastoma at age 33

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: R161X (8684C>T)

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: F56

      Case: Sex unknown, 45Y0M, Spanish

      DiseaseAssertion: assumed VHL

      FamilyInfo: Noted of familial antecedents with 2 affected family members. (See Table 2).

      CasePresentingHPOs: HP:0009711; HP:0006880; HP:0000107 (retinal capillary hemangioma, cerebellar hemangioblastoma, renal cyst)

      CaseHPOFreeText: Age of onset is 45Y0M.

      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.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. GroupID/ KindredID: F54

      Case: Sex unknown, 31Y0M, Spanish

      DiseaseAssertion: assumed VHL

      FamilyInfo: None.

      CasePresentingHPOs: HP:0006880; HP:0000107; HP:0001737 (cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

      CaseHPOFreeText: Age of onset is 31Y0M.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: g.941_943delTCT

      CaseProblemVariantFreeText: Patient was reported with the g. (genomic) coding positions. The g.941_943delTCT variant worked out to correspond with c.227_229delTCT.

      ClinVarID: N/A

      CAID: CA357012 http://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

    3. GroupID/ KindredID: F41

      Case: Sex unknown, 22Y0M, Spanish

      DiseaseAssertion: assumed VHL

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

      CasePresentingHPOs: HP:0009711; HP:0006770; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, clear cell renal cell carcinoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

      CaseHPOFreeText: Multiple lesions were found with the patient’s cerebellar hemangioma. Unilateral ccRCC. Age of onset is 22Y0M.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L128R (c.383T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753891 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.383T%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: L128R (c.383T>G)

      MultipleGeneVariants: N/A

    1. A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB,

      PatientID: D24

      KindredID: 1

      Case: F, 47Y0M, ethnicity unknown

      DiseaseAssertion: cerebellar hemangioblastoma

      FamilyInfo: DNA analysis of other close relatives showed that four clinically unaffected first and second degree relatives (aged 17-77 years) were also carriers of a P81S germline mutation. See Figure 3 for pedigree.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: patient had a single cerebellar HAB

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 8956040; 9829911; 8634692; 17661816 (mentioned as a group)

      SupplementalData: N/A

      Variant: p.P81S (c.241C>T)

      LegacyVariant: p.P81S (c.454C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

      CAID: N/A

      gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P81S (c.241C>T)

      MultipleGeneVariants: N/A

    1. 709 G-->T transversion present in all affected subjects and in four presymptomatic children.

      PatientID: II:7

      KindredID: 1

      Case: M, Age Unknown, Jewish

      DiseaseAssertion: VHL

      FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.

      CasePresentingHPOs: HP:0002666; HP:0006880; HP:0030074 (pheochromocytoma, cerebellar hemangiolastoma, chemodectoma)

      CaseHPOFreeText: patient had cerebellar HB at 25Y, after his initial diagnosis with bilateral pheochromocytoma, and then also extra-adrenal chromafin tumors (carotid body chemodectoma).

      CaseNotHPOs: HP:0005584 (renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 33471715

      SupplementalData: N/A

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

      LegacyVariant: p.V166F (c.709G>T)

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      VariantEvidence: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V166F (c.496G>T)

      MultipleGeneVariants: N/A

    1. 235 (CAG-TAG)1 (1)163HBr, HBc, HBsc, RCC, Cr

      GroupID: None

      Case: Sex Unknown, 63Y0M, Dutch

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009711, HP:0006880, HP:0009713, HP:0005584, HP:0000107 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was published later in PMID 31087189

      SupplementalData: N/A

      Variant: p.R79C (c.235C>T)

      LegacyVariant: c.235 (CAG-TAG)

      CaseProblemVariantFreeText: written in the publication as c.235 (CAG-TAG), deduced to c.235C>T: p.Arg79Cys updated nomenclature

      ClinVarID: 161400 https://www.ncbi.nlm.nih.gov/clinvar/variation/161400/

      CAID: N/A

      gnomAD: 0.00002168, https://gnomad.broadinstitute.org/variant/3-10183766-C-T

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R79C (c.235C>T)

      MultipleGeneVariants: N/A

    2.  c.241C>T2 (2)2a/b47 (34–59)HBr, HBc, HBsc, RCC, pNET, Pheo, Cr

      GroupID:None

      DiseaseAssertion:VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: Dutch

      GroupAgeRange: 34-59

      GroupInfo: 2 out of 82 individuals were grouped together based on all having the c.241C>T mutation. This group was classified as 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.

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

      GroupHPOFreeText: It is unclear if both patients in this group had all of these presentations or if they were only affected by a subset.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P81S (c.241C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

      CAID: N/A

      gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P81S (c.241C>T)

      MultipleGeneVariants: N/A

    1. Case 3 (intradural tumor of T7 spinal nerve roots), which was first thought to be sporadic (non-familial) in 2001, was then re-classified as “HB-only VHLD” (form fruste of VHLD) after the patient’s sister, aged 53, was diagnosed with cerebellar HB (in the sister a germline point mutation and 2 somatic point mutations were found in the DNA of the cerebellar HB, and the case was included as case HB-25 in another study [28]). To the best of our knowledge, this is the first case of a patient with “HB-only VHLD” having clinical expression outside CNS.

      PatientID: N/A

      KindredID: 3

      Case: F, 53Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: Sister was thought to be sporadic (non familial) in 2001 with a spinal T7 tumor - genetic testing in this paper describes her (the sister, case 3) without any mutations.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53. She had a germline point and 2 somatic point mutations found in the DNA of her CHB. These mutations are discussed further in PMID: 24335534

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24335534 (pt. HGB-25)

      SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: P25L(c.74C>T) and D126Rfs*6(c.375_376insA) and E55Rfs(c.163delG)

      MultipleGeneVariants: Somatic, VHL, c.375insA (p.Asp126Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)

    2. Case 3 (intradural tumor of T7 spinal nerve roots), which was first thought to be sporadic (non-familial) in 2001, was then re-classified as “HB-only VHLD” (form fruste of VHLD) after the patient’s sister, aged 53, was diagnosed with cerebellar HB (in the sister a germline point mutation and 2 somatic point mutations were found in the DNA of the cerebellar HB, and the case was included as case HB-25 in another study [28]). To the best of our knowledge, this is the first case of a patient with “HB-only VHLD” having clinical expression outside CNS.

      PatientID: N/A

      KindredID: 3

      Case: F, 53Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: Sister was thought to be sporadic (non familial) in 2001 with a spinal T7 tumor - genetic testing in this paper describes her (the sister, case 3) without any mutations.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53. She had a germline point and 2 somatic point mutations found in the DNA of her CHB. These mutations are discussed further in PMID: 24335534

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24335534 (pt. HGB-25)

      SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

      Variant: p.D126Rfs*6 (c.375_376insA)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573320316 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320316

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: P25L(c.74C>T) and D126Rfs*6(c.375_376insA) and E55Rfs(c.163delG)

      MultipleGeneVariants: Somatic, VHL, c.163delG (p.Glu55Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)

    3. R167Q aminoacidic change (the somatic c.500 G > A substitution is marked by a black arrow).

      PatientID: 1

      KindredID: 1

      Case: F, 40Y0M, Caucasian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006880, HP:0006770, HP:0006748, HP:0001737, HP:0000107, HP:0009713 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Adrenal pheochromocytoma, Pancreatic cysts, Renal cyst, Spinal hemangioblastoma)

      CaseHPOFreeText: The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the   kidney and  pancreas. Clinical symptoms and imaging features include Radicular lumbarpain, lowerlimb paresthesia &weakness/CT, MRI: contrastenhancing masses &erosion of lumbarspine & sacrum.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Normal kidney.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: 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) and I151N (c.452T>A)

      MultipleGeneVariants: Germline, VHL, c. 452T>A (p.Ile151Asn)

    4. R167Q aminoacidic change (the somatic c.500 G > A substitution is marked by a black arrow).

      PatientID: 1

      KindredID: 1

      Case: F, 40Y0M, Caucasian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006880, HP:0006770, HP:0006748, HP:0001737, HP:0000107, HP:0009713 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Adrenal pheochromocytoma, Pancreatic cysts, Renal cyst, Spinal hemangioblastoma)

      CaseHPOFreeText: The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the   kidney and  pancreas. Clinical symptoms and imaging features include Radicular lumbarpain, lowerlimb paresthesia &weakness/CT, MRI: contrastenhancing masses &erosion of lumbarspine & sacrum.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Normal kidney.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVar: 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) and I151N (c.452T>A)

      MultipleGeneVariants: Germline, VHL, c. 452T>A (p.Ile151Asn)

    1. PatientID: None (Maternal Grandmother)

      KindredID: 1

      Case: F, 33Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Look to proband for more information on family history.

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

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 25494863

      SupplementalData: Figure 1

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

      CAID: N/A

      gnomAD:

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114R (c.340G>C)

      MultipleGeneVariants: N/A

    2. PatientID: None (Maternal Aunt)

      KindredID: 1

      Case: F, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Look to proband for more information on family history.

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

      CaseHPOFreeText: Cerebellar/cerebral trunk hemangioblastoma. Multiple retinal hemangioblastomas.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 25494863

      SupplementalData: Figure 1

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

      CAID: N/A

      gnomAD:

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114R (c.340G>C)

      MultipleGeneVariants: N/A

    3. We report the case of a 15-year-old boy with the diagnosis of aggressive GH-PRL pituitary macroadenoma and a family history of VHL disease. Pituitary resection was performed, although complete excision of the lesion could not be confirmed by the neurosurgeon. A control MRI was done 6 months after surgery and the pituitary lesion was similar to the presurgical image. A second operation allowed partial resection of the tumour followed by targeted radiotherapy.

      PatientID: None (Proband)

      KindredID: 1

      Case: M, 18Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The family history revealed VHL in his mother, who died at the age of 40, and in his maternal aunt and grandmother, deceased at 30 and 33 years, respectively. His mother was operated on three times for cerebellar hemangioblastomas, the first at 13 years of age. She had also been treated for bilateral retinal hemangioblastomas since the age of 19. In addition, she had surgery for a renal tumor at the age of 32 and also had pancreatic cysts. She died of the diffuse hemangioblastomas in the posterior fossa. Variant is stated to be previously identified in the family but it is not clear which members have been genetically tested.

      CasePresentingHPOs: HP:0006880; HP:0002893; HP:0007663; HP:0001510; HP:0000823; HP:0009711 (Cerebellar hemangioblastoma, Pituitary adenoma, Reduced visual acuity, Growth delay, Delayed puberty, Retinal capillary hemangioma)

      CaseHPOFreeText: Referred at the age of 15 for decreased visual acuity of the right eye. Growth failure with short stature for age and lack of pubertal development was noted. This was confirmed by ophthal-mologic examination which also showed bitemporal quadranopsia. Two retinal vascular lesions had already been diagnosed and photocoagulated. Cerebral MRI examination visualized a voluminous pituitary adenoma (confirmed pathologically) with suprasellar extension compressing the optic fibres invading both cavernous sinuses. It also confirmed two small cerebellar hemangioblastomas. On follow-up, MRI showed a persistent pituitary adenoma (confirmed by pathology) with numerous mitoses. A cystic part of the main hemangioblastoma was also noted in the right cerebellum image.

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: No renal lesion was found on ultrasound examination. Renal ultrasound examination was persistently normal.

      CasePreviousTesting: N/A

      PreviouslyPublished: 25494863

      SupplementalData: Figure 1

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

      CAID: N/A

      gnomAD:

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114R (c.340G>C)

      MultipleGeneVariants: N/A

    4. PatientID: None (Maternal Aunt)

      KindredID: 1

      Case: F, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Look to proband for more information on family history.

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

      CaseHPOFreeText: Cerebellar/cerebral trunk hemangioblastoma. Multiple retinal hemangioblastomas.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 25494863

      SupplementalData: Figure 1

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

      CAID: N/A

      gnomAD:

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114R (c.340G>C)

      MultipleGeneVariants: N/A

    5. We report the case of a 15-year-old boy with the diagnosis of aggressive GH-PRL pituitary macroadenoma and a family history of VHL disease. Pituitary resection was performed, although complete excision of the lesion could not be confirmed by the neurosurgeon. A control MRI was done 6 months after surgery and the pituitary lesion was similar to the presurgical image. A second operation allowed partial resection of the tumour followed by targeted radiotherapy.

      PatientID: None (Proband)

      KindredID: 1

      Case: M, 18Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The family history revealed VHL in his mother, who died at the age of 40, and in his maternal aunt and grandmother, deceased at 30 and 33 years, respectively. His mother was operated on three times for cerebellar hemangioblastomas, the first at 13 years of age. She had also been treated for bilateral retinal hemangioblastomas since the age of 19. In addition, she had surgery for a renal tumor at the age of 32 and also had pancreatic cysts. She died of the diffuse hemangioblastomas in the posterior fossa. Variant is stated to be previously identified in the family but it is not clear which members have been genetically tested.

      CasePresentingHPOs: HP:0006880; HP:0002893; HP:0007663; HP:0001510; HP:0000823; HP:0009711 (Cerebellar hemangioblastoma, Pituitary adenoma, Reduced visual acuity, Growth delay, Delayed puberty, Retinal capillary hemangioma)

      CaseHPOFreeText: Referred at the age of 15 for decreased visual acuity of the right eye. Growth failure with short stature for age and lack of pubertal development was noted. This was confirmed by ophthal-mologic examination which also showed bitemporal quadranopsia. Two retinal vascular lesions had already been diagnosed and photocoagulated. Cerebral MRI examination visualized a voluminous pituitary adenoma (confirmed pathologically) with suprasellar extension compressing the optic fibres invading both cavernous sinuses. It also confirmed two small cerebellar hemangioblastomas. On follow-up, MRI showed a persistent pituitary adenoma (confirmed by pathology) with numerous mitoses. A cystic part of the main hemangioblastoma was also noted in the right cerebellum image.

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: No renal lesion was found on ultrasound examination. Renal ultrasound examination was persistently normal.

      CasePreviousTesting: N/A

      PreviouslyPublished: 25494863

      SupplementalData: Figure 1

      Variant: p.G114R (c.340G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

      CAID: N/A

      gnomAD:

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114R (c.340G>C)

      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. A female patient presented with VHL disease at age 16, when a symptomatic left adrenal pheochromocytoma was diagnosed and removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. Molecular genetic testing revealed the mutation VHL c.500 G > A (p. R167Q).In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized

      PatientID: 3

      KindredID: 3

      Case: F, 28Y0M, German

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748, HP:0006880, HP:0009713, HP:0030405, HP:0010302 (Adrenal pheochromocytoma, cerebellar hemangioblastoma, spinal hemangioblastoma, pancreatic endocrine tumour, spinal cord tumor)

      CaseHPOFreeText: At age 16 she presented with a left adrenal pheochromocytoma which was removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized. Three of eleven lymph nodes showed metastases.

      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.500G>A)

      MultipleGeneVariants: N/A

    1. 2. Materials and methods2.1. PatientThe 32-year-old male patient was admitted to Xiangya Hospital in 2006 and presented with progressive back and neck pain, and numbness and weakness of both legs which had continued for 1 month followed by fecal and urinary retention for 5 days. The MRI (1.5 Tesla) of the brain and entire spinal cord showed multiple lesions in the cerebellum, brain stem, and spinal cord, which were obviously enhanced and highly suggestive of hemangioblastomas (Fig. 1a–e). Subsequent evaluation, by MRI, of the abdomen revealed a solid kidney tumor (Fig. 1f). He underwent surgical resection for hemangioblastomas of T10 and T12 of the spinal cord, which appeared bright red at surgery. The pathological examination of the tissues showed many small blood vessels, most of which were a capillary plexus. Vascular endothelial cells were flat and distributed within a large number of stromal cells. Some of the vascular endothelial cells formed solid masses and cords. Between the capillary plexus, various forms of stromal cells were found, including nest-like or sheet arrangements with hyperchromatic nuclei, rich cytoplasm, rich lipid vacuoles and rare or no mitoses. Some foam cells and adipose-like cells were also found. Immunohistochemistry of the biopsied tissues from the lesions in the spinal cord were negative on immunostaining (–) for glial fibrillary acidic protein (GFAP), CD68, cytokinin (CK)-pan and epithelial membrane antigen (EMA), but stained positive (+) for factor 8 related antigen (F8RAg). Vascular endothelial cells were F8RAg(+) but stromal cells were F8RAg(–). Vascular endothelial cells and stromal cells were all immunonegative for GFAP, EMA, CK-pan, and CD68 (Fig. 1g, h). The patients’ symptoms resolved after surgery. At 5-year follow-up his condition did not recur or deteriorate, but active surveillance was continued.12Download : Download high-res image (1MB)Download : Download full-size imageFig. 1. Main clinical manifestations of von Hippel-Lindau (VHL) disease. (a) Sagittal T1-weighted MRI of the thoracic spinal cord showing two brightly enhancing nodular lesions with clear boundaries at T10 and T12 (arrows). (b) Sagittal T1-weighted MRI of the cervical spinal cord showing two brightly enhancing nodular lesions with clear boundaries at C5 and C6 (arrows). (c) Sagittal T1-weighted MRI of the cervical spinal cord showing a brightly enhancing nodular lesion with a clear boundary at C2 (arrow). (d) Sagittal T1-weighted MRI of the cranial–cervical region showing three brightly enhancing round lesions with clear boundaries at the posterior of the medulla oblongata, superior spinal cord and basilar part of the pons (arrows). (e) Axial T1-weighted MRI of the brain showing two brightly enhancing nodular lesions with clear boundaries at the posterior of the medulla oblongata and the right cerebellar hemisphere (arrows). (f) Sagittal T1-weighted MRI of the kidney showing the small (1.2 cm × 0.6 cm) enhancing nodular lesion (arrow). (g) Histopathological examination of the lesions at T10 and T12 in the spinal cord of the patient with VHL (hematoxylin and eosin stain, ×400). (h) Immunohistochemistry of the biopsied tissue from the lesions at T10 and T12 in the spinal cord of the patient with VHL (factor 8 related antigen stain, ×400).After genetic counseling, all family members of the patient (his parents, sister, son, sister’s son, brother, and brother’s son) were recruited into this study. His 66-year-old father and 63-year-old mother were both in good health without clinical symptoms of VHL. They did not undergo a whole-body examination, but all other family members underwent clinical examination, including ophthalmoscopy, MRI of the CNS, and ultrasonography of the abdomen, to exclude the disease. Informed consent was obtained from all individuals before their participation in the study.

      PatientID: 1

      KindredID: 1

      Case: M, 39Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history. All 7 of his other family members (his parents, sister, son, sister’s son, brother, and brother’s son) were sequenced and no mutation were found. Additionally, all were healthy members. Suggestive of de novo due to no abnormal changes in the VHL gene of either parent.

      CasePresentingHPOs: HP:0010797; HP:0009713; HP:0006880; HP:0009726 (hemangioblastoma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm)

      CaseHPOFreeText: At 32Y this patient presented with progressive back and neck pain and numbness. Patient developed multiple CNS hemangioblastomas (multiple lesions in the cerebellum, brain stem, and spinal cord). Subsequent evaluation of the abdomen revealed a solid kidney tumor (visceral tumor).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del (c.227_229delTCT)

      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: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229delTCT)

      MultipleGeneVariants: N/A

    1. All family members underwent clinical, laboratory, imaging, and genetic evaluation.

      PatientID: IV-28 [written in Table 2 as IV-24 - typo]

      KindredID: 1

      Case: F, 33Y0M, 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, one of which was this patient who proved to be symptomatic. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

      CasePresentingHPOs: HP:0011732; HP:0006880; HP:0010302 (abnormality of adrenal morphology, cerebellar hemangioblastoma, spinal cord tumor)

      CaseHPOFreeText: Originally thought to be an asymptomatic carrier, however after follow-up was found to be symptomatic: brain MRI revealed multiple tutors, including a frontal mass (cerebellar tumor) with multiple spinal lesions, and an abdominal CT showed a 1.6x1.7 right adrenal mass. Additionally, this patient was pregnant at the time, to which was terminated at the 38th week of gestation with a caesarian section. She has two other children already.

      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. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family

      PatientID: 3

      KindredID: 1

      Case: M, 55Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

      CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0009713; HP:0006880; HP:0001901 (adrenal pheochromocytoma; paraganglioma; pancreatic endocrine tumor; spinal hemagnioblastoma, cerebellar hemagnioblastoma; polycythemia)

      CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 7Y0M. He was found to have adrenal pheochromocytoma; paraganglioma, pancreatic endocrine tumor, spinal and cerebellar hemagnioblastoma, and polycythemia (see table 1). Patient was diagnosed with VHL subtype 2A at 54Y0M.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 8550742

      SupplementalData: N/A

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

      LegacyVariant: N/A

      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: V166F (c.496G>T)

      MultipleGeneVariants: N/A

    2. 16 different families

      PatientID: X-I

      KindredID: 10

      Case: M, 28Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history reported.

      CasePresentingHPOs: HP:0010797; HP:0006880; HP:0009711; HP:0009713; HP:0001737 (hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, spinal hemangioblastoma, pancreatic cyst)

      CaseHPOFreeText: Patient presented with CNS, spinal, retinal and cerebellar hemangioblastoma, as well as a pancreatic cyst at age 28Y0M and was diagnosed with VHL type 2A (see table 2).

      CaseNotHPOs: HP:0000107; HP:0005584; HP:0006748; HP:0002668; HP:0030405 (renal cyst; renal cell carcinoma; adrenal pheochromocytoma; paraganglioma; pancreatic endocrine tumor)

      CaseNotHPOFreeText: Patient negative for renal cyst, renal cell carcinoma, adrenal pheochromocytoma, paraganglioma, and pancreatic endocrine tumor.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: partial deletion (<1kb)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: partial_deletion

      CivicName: NULL (partial deletion)

      MultipleGeneVariants: N/A

    3. 16 different families

      PatientID: IX-I

      KindredID: 9

      Case: M, 68Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history reported.

      CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

      CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

      CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

      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: N/A

      MutationType: deletion

      CivicName: NULL (deletion)

      MultipleGeneVariants: N/A

    4. 16 different families

      PatientID: IX-I

      KindredID: 9

      Case: M, 68Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history reported.

      CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

      CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

      CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

      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: N/A

      MutationType: deletion

      CivicName: NULL (deletion)

      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: 3

      KindredID: A

      Case: Sex Unknown, 35Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: assumed VHL

      FamilyInfo: two other symptomatic and one asymptomatic members of family A had this mutation. The symptomatic individuals had cerebellar hemangioblastomas, as well as spinal hemangioblastomas snd renal cysts.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Symptomatic before 29Y, clinically manifested as >3 cerebellar hemangioblastomas

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 20064270

      SupplementalData: N/A

      Variant: p.F76del (c.227_229del)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: 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: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

      
      
    2. 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: 22

      KindredID: C

      Case: Sex unknown, 30Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: assumed VHL

      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: HP:0006880; HP:0001737; HP:0000107 (cerebellar hemangioblastoma, pancreatic cysts, renal cyst)

      CaseHPOFreeText: Patient had 1 cerebellar HB, pancreatic and kidney cysts.

      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

    3. 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: 2

      KindredID: A

      Case: Sex Unknown, 35Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: assumed VHL

      FamilyInfo: two other symptomatic and one asymptomatic members of family A had this mutation. The symptomatic individuals had cerebellar hemangioblastomas, as well as spinal hemangioblastomas snd renal cysts.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Symptomatic before 35Y, clinically manifested as 3 cerebellar hemangioblastomas

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 20064270

      SupplementalData: N/A

      Variant: p.F76del (c.227_229del)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: 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: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

      
      
    4. 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: 11

      KindredID: C

      Case: Sex Unknown, 45Y0M, Mexican (Latino/Admixed American)

      DiseaseAssertion: assumed VHL

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

      CaseHPOFreeText: Patient had 1 cerebellar HB, pancreatic & kidney cysts, RCC

      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. PatientID: 7

      KindredID: 7

      Case: F, 40Y0M, Ethnicity Unknown

      DiseaseAssertion: Cerebellar Hemangioblastoma

      FamilyInfo: N/A

      CohortInfo: The cohort included a series of 20 capillary haemangioblastomas of the central nervous system for mutations of the VHL gene.

      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.P25L (c.74C>T)

      LegacyVariant: p.P25L (c.287C>T)

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: Refer to Table 1 for abnormal SSCP or heteroduplex patterns.

      MutationType: missense_variant;transition

      CivicName:P25L(c.74C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 9

      KindredID: 9

      Case: M, 18Y0M, Ethnicity Unknown

      DiseaseAssertion: Cerebellar Hemangioblastoma

      FamilyInfo: N/A

      CohortInfo: The cohort included a series of 20 capillary haemangioblastomas of the central nervous system for mutations of the VHL gene.

      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.S183Cfs*19(c.548delC)

      LegacyVariant: p.S183Cfs*19(c.761delC)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA658795184 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

      gnomAD: N/A

      VariantEvidence: Refer to Table 1 for abnormal SSCP or heteroduplex patterns.

      MutationType: minus_1_frameshift_variant

      CivicName: S183fs (c.548delC)

      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

    1. HGB-65 B Germline 3 3 c.517 G > T E173X This study NA NA  

      PatientID: HGB-65

      KindredID: 8

      Case: Sex Unknown, 31Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: None.

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

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

      CaseHPOFreeText: The patient had a multiple cerebellar hemangioblastomas at age 26. The cerebellar hemangioblastomas reoccured at age 29. The patient had a spinal hemangioblastoma at age 30.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.E173* (c.517G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 825515 https://www.ncbi.nlm.nih.gov/clinvar/variation/825515/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: E173* (c.517G>T)

      MultipleGeneVariants: N/A

    2. HGB-19 B/T Germline 2 2 c.341 G > T G114V This study R No  

      PatientID: HGB-19

      KindredID: 4

      Case: Sex Unknown, 44Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: None.

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

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

      CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 32. The patient had a spinal cord hemangioblastoma at age 40.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G114V(c.341G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753604 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.341G%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: G114V (c.341G>T)

      MultipleGeneVariants: N/A

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

      PatientID: HGB-25

      KindredID: 6

      Case: Sex Unknown, 61Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: Positive VHL family history.

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29941223

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType:minus_1_frameshift_variant

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

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

    1. 5 patients with VHL disease (Figs. 1 and 2, and Table 1)

      PatientID: 4

      KindredID: 3

      Case: M, 45Y0M, Arab

      DiseaseAssertion: VHL

      FamilyInfo: No family history of VHL disease was described for this patient. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

      CasePresentingHPOs: HP:0006880; HP:0009713; HP:0000107; HP:0001737; HP:0000787 (cerebellar hemangioblastoma; spinal hemangioblastoma; renal cyst; pancreatic cysts; nephrolithiasis)

      CaseHPOFreeText: At 40Y, Patient 4 was diagnosed with spinal and cerebellar hemangioblastomas, as well as multiple renal and pancreatic cysts. He was diagnosed with VHL disease type 1. At 43Y, renal cysts and stones were discovered. A year later, more spinal hemangioblastomas and renal stones were found. A year later, cerebellar lesions, as well as renal and pancreatic cysts were reported (see table 1).

      CaseNotHPOs: HP:0002088; HP:0001392; HP:0005264; HP:0001743 (abnormal lung morphology; abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

      CaseNotHPOFreeText: No lesions were observed in the lungs, liver, gallbladder, and spleen.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData:  N/A

      Variant: p.N90del (c.268_270del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA645524783, https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA645524783

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: N90del (c.268_270del)

      MultipleGeneVariants: N/A

    2. Patient 1

      PatientID: 1

      KindredID: 1

      Case: M, 51Y0M, Arab

      DiseaseAssertion: VHL

      FamilyInfo: Patient 2 (the patient’s brother) presented with the same mutation and was diagnosed with VHL at age 45. The two brothers had very similar VHL clinical manifestations including cerebellar hemangioblastomas, renal cell carcinoma, and cysts in the pancreas. However, patient 1 had testicular and epididymal cysts, as well as lesions in the spine, which were absent in Patient 2. No other family history was noted. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

      CasePresentingHPOs: HP:0005584; HP:0009713; HP:0006880; HP:0000107; HP:0001737; HP:0030424; HP:0033608; HP:0000541; HP:0012215 (renal cell carcinoma; spinal hemangioblastoma; cerebellar hemangioblastoma; renal cyst; pancreatic cysts; epididymal cyst; pulmonary nodule; retinal detachment; testicular microlithiasis)

      CaseHPOFreeText: At 44Y, Patient 1 exhibited cerebellar and spinal hemangioblastomas, as well as retinal detachment. He also had renal cell carcinoma in both kidneys and multiple cysts in one kidney, testis, and pancreas. He also reported a history of headaches and vertigo, leading to a diagnosis of VHL disease type 1. At 49Y, multiple nodules were found in his lungs and a year later, a nodule in the testis and scrotal lithiasis were detected. At 51Y, renal cell carcinoma was identified in the left kidney and his left epididymis was enlarged. Patient continued to present with left testicular and scrotal lithiasis, right retinal detachment, and multiple nodules in both lungs. However, tMutation:Germlinehe lung phenotype was asymptomatic (see table 1).

      CaseNotHPOs: HP:0001392; HP:0005264; HP:0001743 (abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

      CaseNotHPOFreeText: No lesions were observed in the liver, gallbladder, and spleen.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      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: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/Av

    Tags

    Annotators

    URL

    1. FDaughter1c.160_161delATp.Met54Glyfs*77135–35–35, M35, B–

      PatientID: Daughter

      KindredID: 1

      Case: F, 35Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: Father and brother presented with the same VHL mutation. Brother presented with a meningioma, pancreatic lesions and bilateral renal cysts all at 38Y. Father presented with cerebellar hemangioblastoma 49Y, retinal hemangioblastoma 64Y, bilateral renal cell carcinoma 51Y and multiple pancreatic neuroendocrine tumors 64Y.

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

      CasePresentingHPOs: HP:0006880; HP:0005584; HP:0030405; HP:0000107 (Cerebellar hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst)

      CaseHPOFreeText: Cerebellar hemangioblastoma, renal cell carcinoma, multiple pancreatic neuroendocrine tumors and bilateral renal cysts all at 35Y. Diagnosed with VHL Type 1.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.M54Gfs*77 (c.160_161del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA913189210, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.160_161del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: deletion; minus_2_frameshift_variant

      CivicName: M54Gfs*77 (c.160_161delAT)

      MultipleGeneVariants: N/A

    2. 8M–IVS2c.464-1G > T138–––38, M384

      PatientID: None

      KindredID: 8

      Case: M, 38Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CasePresentingHPOs: HP:0006880; HP:0001737; HP:0000107; HP:0002172; HP:0001288 (Cerebellar hemangioblastoma, Pancreatic cysts, Renal cyst, Postural instability, Gait disturbance)

      CaseHPOFreeText: At 38Y, this patient showed mild imbalance with gait difficulty. MRI of the brain revealed a cystic mass in the cerebellum, which was pathologically found to be hemangioblastoma. When this patient underwent CT, which included the pancreas and kidney, multiple pancreatic cysts and renal cysts were found. Diagnosed with VHL Type 1.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.464-1G>T

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223221, https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant; missense_variant;transversion

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

      MultipleGeneVariants: N/A

    1. CIP35, Bilateral33––Renal cysts and pancreatic cyst1

      PatientID: IP (Proband)

      KindredID: C

      Case: M, 35Y0M, Hungarian

      DiseaseAssertion: VHL

      FamilyInfo: Index patient presented with cerebellar hemangioblastoma, renal cysts, pancreatic cyst and bilateral renal cell carcinomas. Family members were not available for clinical and genetic screening except a brother whose screening revealed no abnormality.

      CasePresentingHPOs: HP:0006880; HP:0005562; HP:0005584; HP:0001737 (Cerebellar hemangioblastoma, Multiple renal cysts, Renal cell carcinoma, Pancreatic cysts)

      CaseHPOFreeText: Patient was operated for cerebellar hemangioblastoma at the age of 33 years. Preoperative clinical screening also showed renal cysts. Two years later, a pancreatic cyst and bilateral renal cell carcinomas were found and the patients underwent bilateral nephrectomy with subsequent chronic hemodialysis. Diagnosed with VHL Type 1.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Heterozygous deletion of Exon 3.

      MutationType: exon_loss_variant

      CivicName: Exon 3 Deletion

      MultipleGeneVariants: N/A

    2. BIP–27–19Renal cysts, pancreatic cysts, and polyglobulia1

      PatientID: None

      KindredID: B

      Case: M, 27Y0M, Hungarian

      DiseaseAssertion: VHL

      FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

      CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

      CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. Case presentationA 35-year-old woman with VHL underwent total pancreatectomy and right nephrectomy for pancreatic SCN and renal cell carcinoma, respectively. At the 4th year follow-up examination after the resection, contrast-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed arterially hyper-enhanced neoplastic lesions in the segment VI and VIII of the liver. Partial resections of the liver were performed 53 months after the initial surgery. At the 6th month follow-up examination from the second surgery, one and two tumors located in the liver segment III, and VIII, respectively, were detected by contrast-enhanced CT and Gd-EOB-DTPA-enhanced MRI. Anterior segmentectomy and partial resection of the segment III were performed 66 months after the initial surgery and 13 months after the second, respectively. The tumors were pathologically diagnosed as liver metastases of pancreatic SCN synonymous with serous cystadenocarcinoma. She remains disease-free without recurrence 6.5 years after the last operation.

      PatientID: 1

      KindredID: 1

      Case: F, 47Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history.

      CasePresentingHPOs: HP:0006880; HP:0002894; HP:0005584 (Cerebellar Hemangioblastoma; neoplasm of the pancreas; renal cell carcinoma)

      CaseHPOFreeText: At 35-year old, the female patient was diagnosed with VHL due to clinical presentation of pancreatic serous cystic neoplasm and renal cell carcinoma, and cerebellar hemangioblastomas that were surgically removed at age 21. The patient had underwent total pancreatectomy and right nephrectomy for pancreatic serous cystic neoplasm (SCN) and renal cell carcinoma (RCC), respectively. 4 years later, tumors in the liver were detected by CT scan and radiographically diagnosed as metasta-ses of the pancreatic SCN or RCC. Again, morphology and immunohistochemical findings of the resected tumors again were similar to the primary pancreatic SCN, thus diagnosed as multiple metachronous liver metastases of pancreatic SCN. As of 47Y, the patient has remained disease-free without any recurrence after the third operation.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 21673464

      SupplementalData: N/A

      Variant: p.N78I (c.233A>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223169 https://www.ncbi.nlm.nih.gov/clinvar/variation/223169/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: N78I (c.233A>T)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 1

      Case: F, 28Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No other family members presented any signs of VHL disease. DNA was available from her sister (32 years), brother (29 years) and mother (55 years). The patient’s father died from a myocardial infarction at the age of 58 years. Suggesting de novo but unclear with no test on father

      CasePresentingHPOs: HP:0010797, HP:0006880, HP:0001737, HP:0009711 (hemangioblastoma, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

      CaseHPOFreeText: at age 28, the patient presented with neurological symptoms from two hemangioblastomas (cerebellar and cerebro-spinal).

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: L140Pfs*4 (c.418dup)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: c.631_632insC

      ClinVar: N/A

      CAID: CA432421871 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.418dup

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: L140fs (c.418dup)

      MultipleGeneVariants: N/A

    1. 1HbCb age 18, Hbs age 19,Hbs age 31Renal cysts 

      PatientID: 1

      KindredID: 1

      Case: M, 31Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Mother with the same variant and presented with breast cancer at age 46 and cerebellar hemangioblastoma and renal cell carcinoma both at age 54. Maternal grandfather (id: 3) presented with cerebellar hemangioblastoma at age 65. Maternal great-uncle (id: 4) presented with prostate cancer at age 65. Maternal great-grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Maternal grandmother and sister did not have the mutation. His maternal grandfather was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

      CasePresentingHPOs: HP:0006880; HP:0009713; HP:0005562 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Multiple renal cysts)

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

      Variant: Exon 1 Deletion (c.1-?_340+?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 Deletion

      MultipleGeneVariants: Germline, FANCD2, Partial Deletion

    2. Interestingly, one carrier of the deletion developed bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma of 1.8 cm size. The tumor was ER- negative, and PR-negative (HER2 was not analyzed). A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. The tumor was classified as T1c pN1a M0, stage IIA; grade G2. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma of 2.0 cm size. The tumor was ER-positive, PR-positive, and HER2-negative. There was no evidence for lymph-node or distant metastases. The tumor was classified as T1c pN 0 M0, stage IA, grade G2 and treated with mastectomy and tamoxifen. Ki67 expression was not tested. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

      PatientID: 2

      KindredID: 1

      Case: F, 54Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

      CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

      CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

      Variant: Exon 1 Deletion (c.1-?_340+?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 Deletion

      MultipleGeneVariants: Germline, FANCD2, Partial Deletion

    3. Interestingly, one carrier of the deletion developed bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma of 1.8 cm size. The tumor was ER- negative, and PR-negative (HER2 was not analyzed). A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. The tumor was classified as T1c pN1a M0, stage IIA; grade G2. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma of 2.0 cm size. The tumor was ER-positive, PR-positive, and HER2-negative. There was no evidence for lymph-node or distant metastases. The tumor was classified as T1c pN 0 M0, stage IA, grade G2 and treated with mastectomy and tamoxifen. Ki67 expression was not tested. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

      PatientID: 2

      KindredID: 1

      Case: F, 54Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

      CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

      CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

      Variant: Exon 1 Deletion (c.1-?_340+?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 Deletion

      MultipleGeneVariants: Germline, FANCD2, Partial Deletion

    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. Von Hippel-Lindau (VHL) is a tumor suppressor that negatively regulates the production of angiogenic factors. Mutations in the VHL gene cause VHL syndrome, which is characterized by highly vascularized tumors. Here we report a c.464T>A mutation of the VHL gene in three patients with hemangioblastoma from a Chinese family. This mutation was not reported previously and was absent in the unaffected family members. The mutation is predicted to cause Val to Glu substitution at VHL protein residue 155 in a conserved region. Previous biochemical studies demonstrated that residue Val-155 was critical for VHL protein binding to chaperonin TRiC/CCT, an essential step for proper VHL protein folding. Our finding of naturally occurring VHL V155E mutation in patients with VHL syndrome supports the functional importance of Val-155 residue in VHL protein and illustrates the diversity of VHL gene defects underlying VHL syndrome.

      PatientID: III-1

      KindredID: 1

      Case: F, 26Y0M, Chinese

      DiseaseAssertion: assumed VHL

      FamilyInfo: 10 members of this Chinese family were tested, and 3 were found with the same genetic mutation (c.464T>A). The proband’s grandmother (I-1, 79Y), and father (II-1, 53Y) had hemangioblastomas, and tested positive for the mutation. This mutation was not found in the other unaffected members in the family.

      CasePresentingHPOs: HP:0006880; HP:0030405; HP:0002666 (cerebellar hemangioblastoma, endolyphmatic sac tumor, pheochromocytoma)

      CaseHPOFreeText: patient suffered with dizziness and headache and frequent vomiting since 25Y (CT and MRI identified occupying lesions and obstructive hydrocephalus in the cerebellar vermis). The cerebellar tumor nodes were removed surgically. Abdominal CT showed multiple lesions in the liver, pancreas and posterior peritoneum. The tumors in the proband’s pancreatic tail and retroperitoneal space also were removed subsequently. Histological analysis indicated the tumors to be pancreatic isletcell tumor and phaeochromocytoma, respectively.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: patient was negative in the bilateral Babinski’s sign test

      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/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V155E (c.464T>A)

      MultipleGeneVariants: N/A

    1. whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB (Fig. 2b,c), renal cell carcinoma and pheochromocytoma.

      PatientID: III-3

      KindredID: 1

      Case: M, 32Y0M, Mexican

      DiseaseAssertion: VHL

      FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

      CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

      CasePresentingHPOs: HP:0006880; HP:0009711; HP:0005584; HP:0002666 (Cerebellar hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma, Pheochromocytoma)

      CaseHPOFreeText: Cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Family pedigree (Figure 1 (a))

      Variant: p.R82P (c.245G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R82P (c.245G>C)

      MultipleGeneVariants: N/A

    1. PatientID: III-9

      KindredID: 1

      Case: F, Age Unknown, Middle Eastern

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: Lacked evidence of any pheos.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    1. This 51-year-old male first presented for workup of headaches and a family history of VHL. He was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs.The patient underwent urgent resection of the largest cerebellar lesion (LHB1) for obstructive hydrocephalus. Following, an oncologic workup was performed, which revealed bilateral RCC (grade III clear cell) requiring total right and partial left sided nephrectomies, pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. A clinical diagnosis of VHL was made, and genetic testing confirmed a genetic mutation of p.R167Q consistent with VHL.

      PatientID: None

      KindredID: 1

      Case: M,53Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: The patient had a family history of VHL.

      CasePresentingHPOs: HP:0006880, HP:0009713, HP:0010797, HP:0000238,HP:0005584, HP:0032241, HP:0030405, HP:0002666 (cerebellar hemangioblastoma, spinal hemangioblastoma, hemangioblastoma, Hydrocephalus, renal cell carcinoma, Cervical neoplasm, pancreatic endocrine tumour, pheochromocytoma)

      CaseHPOFreeText: At age 51, he was found to have three cerebellar hemangioblastomas (two left-sided cerebellar hemangioblastomas (LHB1, LHB2) and one right-sided cerebellar hemangioblastoma (RHB1), two supratentorial hemangioblastomas (right frontal, suprasellar), and multiple spinal HBs including a large left C7-T1 lesion (C7T1), a T5 (T5), right and left sided T11 lesions (RT11, LT11), L2-3 lesion (L23), and multiple small nerve root lesions of the cauda equine consistent with CNS HBs. An oncologic workup revealed bilateral RCC (grade III clear cell), pheochromocytoma requiring adrenalectomy, and a pancreatic neuroendocrine tumor. The patient was subsequently started on Pazopanib. Twelve months following initiation of therapy, the C7T1 HB decreased in size from 14 mm to 12 mm as measured on post-contrast axial T1 MRI. Six months later, C7T1 was further decreased to 9.5 mm, resulting in an approximately 50% decreased volume from initiation of treatment and notably reducing the mass effect on the spinal cord. The L23 lesion also demonstrated reduced size during this time period, from 8 mm to 7.5 mm, while the remaining HBs and retroperitoneal lymph nodes remained stable or increased in size. Following 21 months of TKI therapy, the patient’s systemic disease was stable, and he was placed on a drug holiday. Six months following cessation of Pazopanib, many of the CNS HBs increased slightly, including the C7T1 lesion.

      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.500G>A)

      MultipleGeneVariants: N/A

    1. PMID: 23143947

      PatientID: BII:6

      KindredID: B

      Case: M, 24Y0M (deceased), Chinese

      DiseaseAssertion: cerebellar hemangioblastoma

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant; transition

      CivicName: P154L (c.461C>T)

      MultipleGeneVariants: N/A

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

      PatientID: II-3

      KindredID: 1

      Case: F, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: HP:0005584 (renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: N78D (c.232A>G)

      MultipleGeneVariants: N/A

    1. A 39-year-old man with molecularly confirmed VHL disease presented with epistaxis in 2012. Molecular analysis had confirmed a germline VHL mutation in 2004. He had previously undergone excision of cerebellar haemangioblastoma in 2003. He had also undergone bilateral nephron sparing surgery for ccRCC (stage pT1a, Fuhrman grade up to 3) in 2005 and renal radiofrequency ablation in both 2008 and 2012. CT imaging demonstrated an ethmoid mass measuring 35 × 34 × 44 mm. The patient underwent endoscopic transsphenoidal resection of the lesion. Staging investigations were negative for metastatic disease.Two years later, in 2014, the patient developed symptoms of nasal obstruction. Sinonasal tumour recurrence was suspected. Imaging demonstrated limited progression in the nasal cavity. Excision biopsy was performed. Histology appeared consistent with the initial presenting sinonasal tumour. Excision appeared complete, with no evidence of residual tumour. Subsequently, symptoms recurred. Therapeutic excision was performed in 2015 and again in 2016. To date, the patient's VHL disease remains stable with no evidence of new lesions or metastatic disease.The patient remained under the management of specialist multidisciplinary (MDT) team which coordinated regular imaging surveillance and clinical review. The MDT recommended regular magnetic resonance imaging (MRI) surveillance with localised resection as applicable. More extensive surgery or adjuvant therapy was not felt to be indicated.

      PatientID: None

      KindredID: 1

      Case: M, 39Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006880, HP:0005584; HP:0030072 (Cerebellar hemangioblastoma, clear cell renal cell carcinoma, Paranasal sinus neoplasm)

      CaseHPOFreeText: Previously undergone excision of cerebellar haemangioblastoma in 2003. He had also undergone bilateral nephron sparing surgery for ccRCC (stage pT1a, Fuhrman grade up to 3) in 2005 and renal radiofrequency ablation in both 2008 and 2012. CT imaging demonstrated an ethmoid mass measuring 35 × 34 × 44 mm. The patient underwent endoscopic transsphenoidal resection of the lesion in 2012. Two years later, in 2014, sinonasal tumour recurrence was suspected and imaging demonstrated limited progression in the nasal cavity. Excision biopsy was performed and appeared complete, with no evidence of residual tumour. Subsequently, symptoms recurred. Therapeutic excision was performed in 2015 and again in 2016. To date, the patient's VHL disease remains stable with no evidence of new lesions or metastatic disease.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: Exon 1 Deletion (c.1-?_340+?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 Deletion and c.341-50G>A

      MultipleGeneVariants: Somatic, VHL, c.341-50G>A

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

      PatientID: 1

      KindredID: 1

      Case: F, 25Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

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

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

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

      PatientID: II-a

      KindredID: 1

      Case: F, 16Y0M, Greek

      DiseaseAssertion: Assumed VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

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

      gnomAD: N/A

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

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. 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. 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. Case 11In 1978, an 8-yr-old girl without familial history of VHL was operated for a right pheochromocytoma and at age 13 for a contralateral pheochromocytoma. At age 15, a 4-cm mass at the neck was diagnosed by selective arteriography as a carotid paraganglioma that was removed and histologically confirmed. The patient was then operated twice for cerebellar hemangioblastoma at age 22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was removed. Molecular genetic analysis identified the p.Thr157Ile VHL germline mutation. So far, there are no affected relatives.

      PatientID: 11

      KindredID: 11

      Case: F, 36Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: There was said to be, at the time, no affected relatives

      CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

      CasePresentingHPOs: HP:0006748; HP:0002668; HP:0006476; HP:0006880; HP:0009711; HP:0000618; HP:0010797 (adrenal pheochorocytoma, paraganglioma, abnormality of the pancreatic islet cells, cerebellar hemangioblastoma, retinal capillary hemangioblastoma, blindness, hemangioblastoma)

      CaseHPOFreeText: At 8Y, (in 1978), she was operated for a right pheochromocytoma; at age 13 for a contralateral pheochromocytoma; at age 15, for a 4-cm mass at the neck was diagnosed by selective arteriography as a carotid paraganglioma. The patient was then operated twice for cerebellar hemangioblastoma at age 22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was removed

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.T157I (c.470C>T)

      LegacyVariant: p.T157I

      CaseProblemVariantFreeText: The publication only provides the p., the mutation was able to be deduced to p.T157I (c.470C>T)

      ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: T157I (c.470C>T)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 16

      Case: Sex Unknown, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseHPOFreeText: VHL Type 1.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant; deletion

      CivicName: E189fs (c.565del)

      MultipleGeneVariants: N/A

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

      atientID: None

      KindredID: 15

      Case: Sex Unknown, 71Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseHPOFreeText: VHL Type 2a/b.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 16

      Case: Sex Unknown, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseHPOFreeText: VHL Type 1.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant; deletion

      CivicName: E189fs (c.565del)

      MultipleGeneVariants: N/A

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

      atientID: None

      KindredID: 15

      Case: Sex Unknown, 71Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseHPOFreeText: VHL Type 2a/b.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 24132471

      SupplementalData: Table 1

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. IV - 10

      PatientID: IV:10

      KindredID: 1

      Case: F, 28Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

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

      CaseHPOFreeText: patient had cerebellar HB; renal cysts. Age of onset was 23Y, and surgery (operation) was 28Y

      CaseNotHPOs: HP:0002666; HP:0030405; HP:0001737; HP:0002668 (pheochromocytoma, pancreatic endocrine tumor, pancreatic cysts, paraganglioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    2. IV - 10

      PatientID: IV:10

      KindredID: 1

      Case: F, 28Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

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

      CaseHPOFreeText: patient had cerebellar HB; renal cysts. Age of onset was 23Y, and surgery (operation) was 28Y

      CaseNotHPOs: HP:0002666; HP:0030405; HP:0001737; HP:0002668 (pheochromocytoma, pancreatic endocrine tumor, pancreatic cysts, paraganglioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. 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

    2. 4 16.1 Retinal angioma, cervical spine hemangioblastoma, cysts of pancreas and kidney No Germline G to A base change at −1 position of splice acceptor sequence for exon 2

      PatientID: 4

      KindredID: 4

      Case: 16Y1M, sex unknown ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: None

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

      CaseHPOFreeText: spinal hemangioma was cervical.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.341-1G>A

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 823743 https://www.ncbi.nlm.nih.gov/clinvar/variation/823743/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Germline G to A base change at 1 position of splice acceptor sequence for exon 2

      MutationType: splice_site_variant

      CivicName: Splice Site (c.341-1G>A)

      MultipleGeneVariants: N/A

    1. A 32-year old man was invited to our centre for a consultation at the Polish VHL Registry as a member of a family with suspected von Hippel-Lindau disease (VHL). He had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone. The patient was operated on a few months later and a histopathological diagnosis of choroid plexus papilloma was made. Two years later he was reoperated on due to recurrence and treated with adjunctive radiotherapy. Three years later the patient developed ataxia and was treated surgically because of a cerebellar tumour that was histopathologically diagnosed as haemangioblastoma. Due to recurrence of this tumour the patient was reoperated on two years later. He also had a history of retinal capillary angioma treated by cryo- and laser therapy.

      PatientID: None

      KindredID: 1

      Case: M, 32Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Many of the patient’s family members developed lesions in sites suggesting VHL including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and some of the family members have lost their sight because of retinal detachment (probably in the case of retinal haemangiomas). However, the diagnosis of VHL has not been established in the family. Two of his children were also found to have the NM_000551.3:c.194C>T(S65L) mutation after analysis of blood samples.

      CasePresentingHPOs: HP:0030393; HP:0010797; HP:0009711 (Endolymphatic sac tumour, hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: The patient had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone with a recurrence two years later (at 21Y). The patient was originally histopathologically diagnosed with choroid plexus papilloma, but was re-diagnosed with an endolymphatic sac tumour on reexamination of the sample. Three years later (24Y) the patient developed ataxia because of a cerebellar tumour that was histopathologically diagnosed as hemangioblastoma. He had a recurrence two years later (26Y). He also had a history of retinal capillary angioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.S65L (c.407C>T)

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

      gnomAD: 0.000, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    2. A 32-year old man was invited to our centre for a consultation at the Polish VHL Registry as a member of a family with suspected von Hippel-Lindau disease (VHL). He had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone. The patient was operated on a few months later and a histopathological diagnosis of choroid plexus papilloma was made. Two years later he was reoperated on due to recurrence and treated with adjunctive radiotherapy. Three years later the patient developed ataxia and was treated surgically because of a cerebellar tumour that was histopathologically diagnosed as haemangioblastoma. Due to recurrence of this tumour the patient was reoperated on two years later. He also had a history of retinal capillary angioma treated by cryo- and laser therapy.

      PatientID: None

      KindredID: 1

      Case: M, 32Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: Many of the patient’s family members developed lesions in sites suggesting VHL including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and some of the family members have lost their sight because of retinal detachment (probably in the case of retinal haemangiomas). However, the diagnosis of VHL has not been established in the family. Two of his children were also found to have the NM_000551.3:c.194C>T(S65L) mutation after analysis of blood samples.

      CasePresentingHPOs: HP:0030393; HP:0010797; HP:0009711 (Endolymphatic sac tumour, hemangioblastoma, retinal capillary hemangioma)

      CaseHPOFreeText: The patient had a history of left facial nerve palsy at the age of 19 years due to tumour of the temporal bone with a recurrence two years later (at 21Y). The patient was originally histopathologically diagnosed with choroid plexus papilloma, but was re-diagnosed with an endolymphatic sac tumour on reexamination of the sample. Three years later (24Y) the patient developed ataxia because of a cerebellar tumour that was histopathologically diagnosed as hemangioblastoma. He had a recurrence two years later (26Y). He also had a history of retinal capillary angioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.S65L (c.407C>T)

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

      gnomAD: 0.000, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

  2. Jul 2026
    1. Complete deletion

      GroupID/ KindredID: 28

      PatientID: II

      Case: 24Y0M, Sex unknown, Polish

      DiseaseAssertion: VHL

      FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

      GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: complete deletion of VHL gene

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Haplotype analysis information in Table 3

      MutationType: deletion

      CivicName: deletion

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: F28

      Case: Sex unknown, 23Y0M, Spanish

      DiseaseAssertion: assumed VHL

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

      CasePresentingHPOs: HP:0000107; HP:0009711; HP:0006880; HP:0006770; HP:0002666 (renal cysts, retinal capillary hemangioma, cerebellar hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma)

      CaseHPOFreeText: unilateral pheo, bilateral ccRCC and multiple lesions were found with the patient’s renal cysts. Age of onset is 23Y0M.

      CaseNotHPOs: HP:0001737 (pancreatic cysts)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: rearrangement (unspecified)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Southern blot positive

      MutationType: rearrangement_region

      CivicName: Rearrangement

      MultipleGeneVariants: N/A

    1. 16 different families

      PatientID: IX-I

      KindredID: 9

      Case: M, 68Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history reported.

      CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

      CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

      CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

      CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

      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: N/A

      MutationType: deletion

      CivicName: NULL (deletion)

      MultipleGeneVariants: N/A