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    1. M2)

      Case#: Patient M2, Muslim religious group, located in lower Galilee.

      DiseaseAssertion: MPS1-H

      FamilyInfo: Parents of M2 were found to be heterozygous for this mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations T.A. Vasilyeva,  T.A. Vasilyeva Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian FederationSearch for more papers by this authorA.A. Voskresenskaya,  A.A. Voskresenskaya Department of Ambulant Surgery and Conservative Treatment, Cheboksary Branch of S. Fyodorov Eye Microsurgery Federal State Institution, Cheboksary, Russian FederationSearch for more papers by this authorB. Käsmann-Kellner,  B. Käsmann-Kellner German Aniridia Center at the Section of Pediatric Ophthalmology, Orthoptics, Low Vision & Neuroophthalmology, Department of Ophthalmology, Saarland University Homburg/Saar, GermanySearch for more papers by this authorO.V. Khlebnikova,  O.V. Khlebnikova Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian FederationSearch for more papers by this authorN.A. Pozdeyeva,  N.A. Pozdeyeva Department of Ambulant Surgery and Conservative Treatment, Cheboksary Branch of S. Fyodorov Eye Microsurgery Federal State Institution, Cheboksary, Russian FederationSearch for more papers by this authorG.M. Bayazutdinova,  G.M. Bayazutdinova Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian FederationSearch for more papers by this authorS.I. Kutsev,  S.I. Kutsev Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian Federation Department of Molecular and Cell Genetics, Pirogov Russian National Research Medical University, Moscow, Russian FederationSearch for more papers by this authorE.K. Ginter,  E.K. Ginter Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian FederationSearch for more papers by this authorE.V. Semina,  E.V. Semina Division of Developmental Biology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WisconsinSearch for more papers by this authorA.V. Marakhonov,  Corresponding Author A.V. Marakhonov marakhonov@generesearch.ru orcid.org/0000-0002-0972-5118 Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian Federation Laboratory of Functional Analysis of the Genome, Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russian Federation Correspondence Rena A. Zinchenko, Andrey V. Marakhonov, Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moskvorechie Street, 1, 115478 Moscow, Russian Federation. Email: renazinchenko@mail.ru, marakhonov@generesearch.ruSearch for more papers by this authorR.A. Zinchenko,  Corresponding Author R.A. Zinchenko renazinchenko@mail.ru Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moscow, Russian Federation Department of Molecular and Cell Genetics, Pirogov Russian National Research Medical University, Moscow, Russian Federation Correspondence Rena A. Zinchenko, Andrey V. Marakhonov, Federal State Budgetary Institution ‘Research Center for Medical Genetics’, Moskvorechie Street, 1, 115478 Moscow, Russian Federation. Email: renazinchenko@mail.ru, marakhonov@generesearch.ruSearch for more papers by this author

      PMID 28321846

      Gene: PAX6

      Variant NM_001368894.2:c.-128-2del

      Disease: Ocular dysgenesis

      InheritancePattern: AD

      Disease PAX6-related ocular dysgenesis MONDO:0800183

      Proband 26.03 and apparently de novo

    1. PMID: 23143947

      PatientID: DII2

      KindredID: D

      Case: M, 37Y0M (deceased), Chinese

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: A 3-generation family is given with 3 confirmed members with this mutation. 2 other members had VHL-presenations however had not been tested for the gene.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: died of multiple central nervous system hemangioblastoma at the age of 37 without operation.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.F76del (c.226_228delTTC) [assumed]

      LegacyVariant: p.F76del (c.439delTCT)

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

      ClinVarID: N/A

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

      gnomAD: N/A

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

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229delTCT)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 2

      Case: Sex Unknown, Age Unknown, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 8634692

      SupplementalData: N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: c.437_439del

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: Variant reported as c.437_439del and mapped to c.224_226del which is equivalent to c.227_229del.

      MutationType: inframe_deletion; deletion

      CivicName: F76del (c.224_226delTCT)

      MultipleGeneVariants: N/A

    1. IVS1+1G>A Splice Germline mutation

      PatientID: 37

      KindredID: 37

      Case: Age, sex, ethnicity unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+1G>A

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

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

      MultipleGeneVariants: N/A

    1. in seven of the asymptomatic family members.

      PatientID: II-7

      KindredID: 1

      Case: M, Age Unknown, Turkish

      DiseaseAssertion: asymptomatic

      FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s 3 siblings had the mutation, one of her children, and more. See Fig. 1 for full family pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: None - described as a carrier of the p.A149S mutation, with no clinical manifestations. Their asymptomatic work up could have been due to the individual's young age

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.A149S (c.445G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: A149S (c.445G>T)

      MultipleGeneVariants: N/A

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

      GroupID/ KindredID: 1255NCI

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151; 9829911

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: W88R (c.262T>A)

      MultipleGeneVariants: N/A

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

      GroupID/ KindredID: 51CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

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

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

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: N78H (c.232A>C)

      MultipleGeneVariants: N/A

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

      GroupID/ KindredID: 141CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 141CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: FS (c.776delT)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

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

      MutationType: minus_1_frameshift_variant

      CivicName: L188fs (c.563delT)

      MultipleGeneVariants: N/A

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

      GroupID/ KindredID: 3315NCI, 127CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 7728151; 9829911

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: frameshift_variant; transition

      CivicName: S111N (c.332G>A)

      MultipleGeneVariants: N/A

    1. PatientID: Carrier 11 (father to proband 7)

      KindredID: 3

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Father, mother and sister (all relative to proband 7) had this variant. Both father and sister were asymptomatic. Proband and mother presented with unilateral PCC.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P138Afs*6 (c.410dup)

      LegacyVariant: 623insTTTGTtG

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup

      gnomAD: N/A

      VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.

      MutationType: insertion; plus_1_frameshift_variant

      CivicName: P138fs (c.410dup)

      MultipleGeneVariants: N/A

    2. PatientID: Carrier 6 (nephew to proband 3)

      KindredID: 1

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.H125P (c.374A>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: H125P (c.374A>C)

      MultipleGeneVariants: N/A

    1. 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

    2. 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

    3. 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

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

      PatientID: HGB-25

      KindredID: 6

      Case: Sex Unknown, 61Y0M, Italian

      DiseaseAssertion: VHL

      FamilyInfo: Positive VHL family history.

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

      CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29941223

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType:minus_1_frameshift_variant

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

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

    1. 2 (100)

      GroupID: 13

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: These 2 patients with a R161* (c.481C>T) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      GroupProblemVariantFreeText: 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. VHL (n = 10)

      PatientID: N/A

      KindredID: 10

      Case: M, 23Y0M, Ethnicity Unknown

      DiseaseAssertion: pheochromocytoma and paraganglioma

      FamilyInfo: No family information provided.

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

      CaseHPOFreeText: Patient is a white 23Y0M male diagnosed with either pheochromocytoma and paraganglioma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: See table s3 for patient-related information.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

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

      PatientID: N/A

      KindredID: 1

      Case: M, 34Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: R161Q (c.695G>A)

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. Case I:2 (the proband’s mother)

      PatientID: I:2

      KindredID: 1

      Case: F, Age Unknown, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: Case III:1 (this patients daughter) was a 32 year old female who complained of blurred vision for the past 2 years in her left eye. Fundus examinations showed several retinal hemangioblastomas in the temporal area of the left eye. They had previously undergone the operation for cerebellar hemangioblastoma 3 years prior. Case III:2 (this patient’s grandson) was a 6 year old male who had fundus examination that revealed a very small hemangioblastoma in the distant peripheral retina of his right eye, while his left eye was normal. Case III:2 (this patient’s granddaughter) was a 12 year old female whose fundus examinations revealed a small hemangioblastoma in the infratemporal region of the peripheral retina in her right eye. A sizeable hemangioblastoma with 2.5 papilla diameters and prominant feeder vessels were detected in the inferior peripheral retina of her left eye

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: had blindness in one eye and died of renal carcinoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_transversion

      CivicName: W117R (c.349T>A)

      MultipleGeneVariants: N/A

    1. 5

      PatientID: III-3

      KindredID: 1

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: In the patient’s 12 member Chinese family, 7 members were found to carry the NM_000551.3:c.114delC mutation. Five had manifestations of CNS hemangioblastoma, and three of the five were deceased. The other two members found to carry the mutation were asymptomatic, although the paper states that this is likely due to their young age.

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: The patient suffered from progressive severe neck pain and numbness of the left arm for 6 months. The patient was initially treated with opioids and antiinflammatory medications and wore rigid neck collars. Despite intense conservative therapy, the patient experienced inadequate pain relief and underwent resection of CNS hemangioblastoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G39Afs*28(c.114delC)

      LegacyVariant: p.G39Afs*28(c.327delC)

      ClinVarID: N/A

      CAID: CA2573047816, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA2573047816

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: G39Afs(c.114delC)

      MultipleGeneVariants: N/A

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

      GroupID: 34

      Case: Sex unknown, Age unknown, French

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    2. 2 Germany c.463+2T>C splice

      GroupID: 20

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      GroupInfo: 2 registrants from Germany were grouped in this study via the mutation of c.463+2T>C

      GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      GroupHPOFreeText: N/A

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.463+2T>C

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 569414 https://www.ncbi.nlm.nih.gov/clinvar/variation/569414/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Site (c.463+2T>C)

      MultipleGeneVariants: N/A

    1. PatientID: None (Proband)

      KindredID: 1

      Case: F, 49Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 237

      KindredID: 89

      Case: F, 46Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

      Variant: c.642+70C>T

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

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

      MultipleGeneVariants: N/A

    2. PatientID: 60

      KindredID: 23

      Case: M, 30Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband (patient 23) had three family members genetically confirmed with the mutation: his son/ patient 61 (asymptomatic at time of assessment), his daughter/ patient 62 (asymptomatic at time of assessment), and his cousin/ the son of his Aunt 3/ patient 68 (CNS hemangioblastoma at 26). The proband also had 5 family members who passed away before they could be confirmed with the mutation: his father/patient 63 (CNS hemangioblastoma at 35, retinal angioma at 35); his sister/ patient 64 (CNS hemangioblastoma at 24 and multiple pancreatic cysts/tumors at 31); his aunt 1/ patient 65 had a CNS hemangioblastoma at 35; his aunt 2/ patient 66 had a CNS hemangioblastoma at 20; and his aunt 3/ patient 67 had a CNS hemangioblastoma at 44.

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

      CaseHPOFreeText: The proband presented with CNS hemangioblastoma and retinal angioma at 25, renal cell carcinoma and multiple pancreatic cysts/tumors at 30.

      CaseNotHPOs: HP:0002666 (Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

      Variant: p.W88S (c.263G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2220; https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/?new_evidence=true

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W88S (c.263G>C)

      MultipleGeneVariants: N/A

    1. GroupID: 31

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 4 members of this family were found to harbor the c.531_532ins18 germline variant of the VHL gene. Member 2656 had unknown renal involvement. Members 2511, 4325, 2744 and 2668 presented with mild renal disease (RCC). Members 2588, 2746 and 4630 presented with moderate renal disease (RCC). Members 2060 and 2279 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

      GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 9829912, where 3 individuals with this mutation are reported. It is unclear which of the previously reported individuals corresponds to which individuals of the current family.

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

      Variant: p.L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573130363, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130363

      gnomAD: N/A

      VariantEvidence: Variant is reported in the current manuscript as “c.531_532ins18” and as “c.531_532insCTGAGAGTAAAGCCTGAA” in the previously published PMID 9829912.

      MutationType: inframe_insertion

      CivicName: L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

      MultipleGeneVariants: N/A

    2. GroupID: 503

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    3. GroupID: 333

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 2 members of this family presented with the c.500G>A germline variant of the VHL gene. Member 9428 presented with mild renal disease. Member 13001 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 10 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously reported individuals/families could alternatively correspond to family 262, 36 or 509.

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    4. GroupID: 185

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 4 members of this family are reported as carrying the c.193T>C germline variant of the VHL gene. Member 9359 has unknown renal involvement. Member 9357 presented with mild renal disease. Member 1052 had no renal involvement. Member 3979 has moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 2 patients with this mutation are reported but relation between patients is unknown.

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

      Variant: p.S65P (c.193T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 547829, https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65P (c.193T>C)

      MultipleGeneVariants: N/A

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

      PatientID: 4

      KindredID: 4

      Case: F, 53Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

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

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S111N (c.332G>A)

      MultipleGeneVariants: N/A

    1. 4 Missense p.(Asn78Ser) 1 0

      GroupID: 4

      DiseaseAssertion: VHL

      Group size: 1

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. GroupID: 11

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: N/A

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

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G93_Y98del (c.277_294del)

      LegacyVariant: c.488_490del18bp

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA891843321, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275_292del

      gnomAD: N/A

      VariantEvidence: Variant reported as c.488_90del18bp and mapped to c.275_292del (equivalent to c.277_294del).

      MutationType: deletion; inframe_deletion

      CivicName: G93_Y98del (c.275_292del)

      MultipleGeneVariants: N/A

    1. PatientID: 100

      KindredID: 100

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Paraganglioma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002668 (paraganglioma)

      CaseHPOFreeText: The patient had multiple paragangliomas.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Patient information pulled from Supplemental Table 1. There is additional tumour specific information in Supplemental Table 2.

      Variant: p.R64P (c.191G>C)

      ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

      gnomAD: N/A

      VariantEvidence: Membrane CA9 immunostaining was observed (supplemental table 1).

      MutationType: missense_variant;transversion

      CivicName: R64P(c.191G>C)

      MultipleGeneVariants: N/A

    2. PatientID: 40/41

      KindredID: 40/41

      Case: Sex Unknown, 15Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Multiple benign PCC.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Patient information pulled from Supplemental Table 1a.

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Patient data is extracted from two rows assumed to be referring to the same patient (i.e. tumor samples 40 and 41 in Supplementary Table 1a). Carbonic anhydrase 9 (CA9) mRNA level of 795.70 (PCC) and 815.38 (PCC) were detected. Membrane CA9 immunostaining was observed in both PCC samples.

      MutationType: missense_variant;transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    1. detected point germline vhl mutations in 14 patients

      PatientID: 23

      KindredID: 23

      Case: 23Y0M, sex unknown, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0030393; HP:0005584; HP:0009711 (hemangioblastoma; endolymphatic sac tumor; renal cell carcinoma; retinal capillary hemangioma)

      CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: 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; transversion

      CivicName: N78I (c.233A>T)

      MultipleGeneVariants: N/A

    1. Case 2 was a 7-yr-old boy, diagnosed with a malignant sympathetic paraganglioma in the retroperitoneum with regional lymph node metastases, who presented with a parasympathetic paraganglioma of the left carotid body 8 yr later. Genetic testing revealed the VHL p.Tyr98His mutation, which has also been described previously (15). In addition hemangioblastomas and pheochromocytomas were found in family members.

      PatientID: 2

      KindredID: 2

      Case: M, 15Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history revealed hemangioblastomas and pheochromocytomas.

      CohortInfo: Two patients with parasympathetic paraganglioma, previously published in 19336503 were studied.

      CasePresentingHPOs: HP:0002668 (paraganglioma)

      CaseHPOFreeText: At age 7, the patient had a malignant sympathetic paraganglioma in the retroperitoneum with regional lymph node metastases. Eight years later, the patient presented with a parasympathetic paraganglioma of the left carotid body.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No other tumours were found.

      CasePreviousTesting: SDHB/SDHC/SDHD

      PreviouslyPublished: 19336503

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

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

      VariantEvidence: Case 2 showed LOH for markers D3S1597 and D3S1263 and was homozygous (not informative) for marker D3S1435.

      MutationType: missense_variant; transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. c.496_506del11 (p.Val166Serfs*4) in seven individuals, belonging to two pedigrees.

      PatientID: 65

      KindredID: 65

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867 (likely family 17 - see here for more info)

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

      Variant: p.V166Sfs*4 (c.496_506del11)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223229 https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift_variant

      CivicName: V166Sfs*4 (c.496_506del)

      MultipleGeneVariants: N/A

    2. 35 (45%) had missense variants,

      PatientID: 3

      KindredID: 3

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: D92V (c.275A>T)

      MultipleGeneVariants: N/A

    3. 35 (45%) had missense variants

      PatientID: 16

      KindredID: 16

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

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

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

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

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    4. 86 VHL patients

      PatientID: 58

      KindredID: 58

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL (asymptomatic)

      FamilyInfo: N/A

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867

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

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. PatientsThe Chinese family study included five-generations comprising of 38 living family members, of whom nine were affected [Figure 1]. All living members were examined clinically. The clinical and radiographic images were published with the consent of the patient. The study was approved by the research Ethics Committees of Xi’an Jiaotong University School of Medicine. Written informed consents were obtained from all participants.Open in a separate windowFigure 1Haplotypes of the Chinese family affected by Von Hippel-Lindau (VHL). The open and filled blackened symbols indicated unaffected and affected individuals, respectively. The squares and circles symbolized the males and females, respectively. The proband, IV-3, was indicated by an arrow. The haplotyping was conducted using three polymorphic microsatellite markers. The marker order was determined from the Marshfield map and the UCSC Human Genome database (February 2009). The dark boxes symbolized haplotypes that cosegregated with the affected individuals and suggested linkage of VHL to disease in this family. The boxes with slash symbolized the dead family members.

      PatientID: II:4

      KindredID: 1

      Case: F, Age Unknown (deceased), 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: N/A

      CaseHPOFreeText: unknown phenotype, however they were said to be affected

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: 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: Death before genetic diagnostic, however presumed by authors due to extensive family history (See pedigree).

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. 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. VHL_2Frozenc.250G>Tp.Val84LeuM25AdrenalPCCB

      PatientID: VHL_2 (tumor ID)

      KindredID: 2

      Case: M, 25Y0M, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 25Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V84L (c.250G>T)

      MultipleGeneVariants: N/A

    1. PatientID: N/A

      KindredID: 198

      Case: Age unknown, Sex unknown, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Paper states: Germline, de novo

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes (Specifically Supp. Table S2)

      Variant: p.W117Cfs*42 (c.351del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: paper states c.350delG which automaps to NM_000551.3:c.351delG

      ClinVarID: 223197 https://www.ncbi.nlm.nih.gov/clinvar/variation/223197/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: W117fs (c.351del)

      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. 462A→C Tv Exon 2 154 CCA P P154P

      GroupID: 35

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.P154P (c.462A>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA16621934 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.462A%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: synonymous_variant

      CivicName: P154= (c.462A>C)

      MultipleGeneVariants: N/A

    2. 481C→T Ts Exon 3 161 CGA R R161X

      GroupID: 43

      DiseaseAssertion: VHL

      GroupSize: 8

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 8 patients are listed with this mutation; any relation is unknown.

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      GroupHPOFreeText: 3 members are stated to have retinal HBs. Other manifestations are possible but not clear.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: the other 5 patients are said to not have retinal HBs

      GroupPreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      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

    3. 395A→C Tv Exon 2 132 CAA Q Q132P

      GroupID: 31

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: N/A

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

      Variant: p.Q132P (c.395A>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 496063 https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: Q132P (c.395A>C)

      MultipleGeneVariants: N/A

    4. 563T→C Ts Exon 3 188 CTG L L188P

      GroupID: 51

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L188P (c.563T>C)

      MultipleGeneVariants: N/A

    1. GroupID: 3003

      DiseaseAssertion: assumed VHL

      GroupSize: 27

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Familial VHL stated; 27 family members recorded with this mutation.

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

      GroupHPOFreeText: 11/27 members had retinal angioma (hemangioma), 9 had CNS hemangioblastoma, and 5 had RCC

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040 (type 1 3003NCI); 9829911

      SupplementalData: N/A

      Variant: p.S168Ifs*5 (c.502_503insTTGTTCGT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.239fs (c.715insTTGTTCGT)

      ClinVarID: N/A

      CAID: CA2573051075 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051075

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_2_frameshift_variant

      CivicName: S168fs (c.502_503insTTGTTCGT)

      MultipleGeneVariants: N/A

    2. GroupID: 3568

      DiseaseAssertion: assumed VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

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

      GroupHPOFreeText: 1 member stated with an angioma (retinal hemangioma), 2 members have CNS hemangioblastoma, 4 with RCC.

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 19464396

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

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

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

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: P86L (c.257C>T)

      MultipleGeneVariants: N/A

    3. PatientID: None

      KindredID: 3760

      Case: Sex, Age, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 8956040

      SupplementalData: N/A

      Variant: p.Y112* (c.336C>A)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.Y183* (c.549C>A)

      ClinVarID: N/A

      CAID: CA16602183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.336C%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: Y112* (c.336C>A)

      MultipleGeneVariants: N/A

    4. GroupID: 3786

      DiseaseAssertion: assumed VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

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

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

      GroupNotHPOs: HP:0005584 (renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: 8956040

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    1. The tests revealed that the same missense mutation in the VHL gene [c.500G>A (p.Arg167Gln)] was found in the patient and his two sons

      PatientID: III-6

      KindredID: 3

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: The patient's father, the proband (II-4) carried the VHL mutation and presented with clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, and renal cysts. The patient's brother (III-7) carried the mutation but was asymptomatic. The patient's grandmother (I-2) died as a result of pancreatic cancer. His paternal aunt (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another paternal aunt (II-2) underwent surgery for breast cancer. See Figure 3 for family pedigree.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Abdominal ultrasound examination of the patient revealed no abnormality.

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

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: F11

      Case: Sex unknown, 32Y0M, Spanish

      DiseaseAssertion: assumed VHL

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

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

      CaseHPOFreeText: Multiple lesions were found with the patient’s retinal hemangioma. Bilateral pheo. Age of onset is 32Y0M.

      CaseNotHPOs: HP:0006770; HP:0000107; HP:0006880; HP:0001737 (clear cell renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, pancreatic cysts)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y175N (c.523T>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756226 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: Y175N (c.523T>A)

      MultipleGeneVariants: N/A

    1. 8 M c.446A>C (N78T) Bilateral Positive (CNS) Positive 

      PatientID: 8

      KindredID: 8

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0000107; HP:0005584; HP:0010797; HP:0001737 (Renal cyst, Renal cell carcinoma, Hemangioblastoma, Pancreatic cysts)

      CaseHPOFreeText: Bilateral RCC and renal cysts, CNS hemangioblastoma, positive for pancreatic cysts.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table 1

      Variant: p.N78T (c.233A>C)

      LegacyVariant: c.446A>C (N78T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223168, https://www.ncbi.nlm.nih.gov/clinvar/variation/223168/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant is declared as “c.446A>C (N78T)” by the authors, this was treated as a legacy variant and mapped to c.233A>C, N78T. This study found coexpression of Epo and EpoR in 11 RCCs and in 10 benign renal cysts in a spectrum of VHL renal disease suggesting that Epo/EpoR coexpression is present in both benign and malignant stages of renal neoplasia. Six benign cysts stained for Epo but not EpoR. The researchers detected loss of heterozygosity of a wild-type VHL allele in different RCCs with microsatellite markers, D3S1110 and D3S2452, flanking the VHL gene

      MutationType: missense_variant;transition

      CivicName: N78T (c.233A>C)

      MultipleGeneVariants: N/A

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

      PatientID: 2

      KindredID: 1

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

      DiseaseAssertion: VHL

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

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

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G114S (c.340G>A)

      MultipleGeneVariants: N/A

    1. PatientID: 6

      KindredID: 6

      Case: M, 45Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history but no further details were provided. CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

      CasePresentingHPOs: HP:0009711; HP:0006748 (Retinal capillary hemangioma, Adrenal pheochromocytoma)

      CaseHPOFreeText: Diagnosed with VHL type 2A. Right adrenal pheochromocytoma (41Y) and retinal angioma. No metastasis. Last follow-up 4 years after diagnosis.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: c.547T>C

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Authors report variant as “547, T to C”. Assumed to be reported in legacy nomenclature (AF010238.1 (Latif et al.)) and mapped to c.334T>C (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    1. Patient 2 The second patient had a familial history of VHL disease but had never been screened for central nervous system manifestations when she experienced a sudden left hearing loss at 18 years old. The MRI revealed a left mass of the temporal bone invading the otic capsule but without extension in the cerebellopontine angle (Fig. 1) and also a cystic hemangioblastoma of the brainstem with significant mass burden but no associated symptoms. It was decided to operate on the hemangioblastoma first due to its size and location and the endolymphatic sac tumor remained under surveillance. The MTD of the endolymphatic sac tumor at diagnosis was 1.9 cm. Apart from central nervous systems hemangioblastomas, the patient developed pancreatic cysts in the course of her VHL disease. The germline mutation of the VHL gene was also identified (c.345C>G, p.His115Gln). During 18 years of surveillance, the tumor increased in size following a two-phase growth pattern alternating phases of quiescence and phases of continuous growth (Fig. 2). Apart from her left cophosis, she did not suffer from any vestibular symptoms and the rest of her neurological exam remained normal. As tumor did not develop in the cerebellopontine angle and did not threaten the brainstem, it was decided to postpone surgery and the patient remains under surveillance.

      PatientID: 2

      KindredID: 2

      Case: F, 36Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: familial history of VHL disease

      CasePresentingHPOs: HP:0030393; HP:0010797; HP:0001737 (endolymphatic sac tumor, hemangioblastoma, pancreatic cysts)

      CaseHPOFreeText: at 18Y experienced a sudden left hearing loss (MRI revealed hemangioblastomas of the temporal bone invading the otic capsule; operated on; the MTD of the endolymphatic sac tumor at diagnosis was 1.9 cm). The patient also developed pancreatic cysts.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.H115Q (c.345C>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496058 https://www.ncbi.nlm.nih.gov/clinvar/variation/496058/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: H115Q (c.345C>G)

      MultipleGeneVariants: N/A

    1. GroupID: 5

      Case: M, Age unknown, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: W88R (c.262T>A)

      MultipleGeneVariants: N/A

    2. GroupID: 9

      Case: M, Age unknown, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: Unknown

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: Minus_1_frameshift_variant

      CivicName: R176Gfs (c.526del)

      MultipleGeneVariants: N/A

    1. 22a4Fc.499C>T3Missensep.Arg167Trp8P, muAsynchronous

      PatientID: 22

      KindredID: 4

      Case: F, 8Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Four members of this family, IDs #22 (8Y, F), #23 (25Y, M), #24 (14Y, M), #25 (12Y, M), were found to have the same variant and pheochromocytoma.

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

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Asynchronous multifocal pheochromocytoma. 8Y at VHL diagnosis.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. c.463 + 8C > T (intron 2)

      PatientID: None

      KindredID: 6

      Case: Sex, Age, Ethnicity unknown

      DiseaseAssertion: dilatation of the cerebral artery

      FamilyInfo: None

      CasePresentingHPOs: HP:0004944 (dilatation of the cerebral artery)

      CaseHPOFreeText: Patient had an intracranial aneurysm

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.463+8C>T

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 127830 https://www.ncbi.nlm.nih.gov/clinvar/variation/127830/

      CAID: N/A

      gnomAD: 0.0005055 https://gnomad.broadinstitute.org/variant/3-10188328-C-T

      VariantEvidence: N/A

      MutationType: splice_site_variant

      CivicName: Splice Region (c.463+8C>T)

      MultipleGeneVariants: N/A

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

      PatientID: IV-17

      KindredID: 1

      Case: M, 16Y0M, Iranian

      DiseaseAssertion: assumed VHL

      FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Patient had a unilateral PCC at 14Y which was surgically removed at the time. Histopathology was benign, and there was no case of relapse or metastatic dissemination.

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

      PatientID: I.2

      KindredID: F8

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+648T>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant;transition; splice_site_variant

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

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

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

      PatientID: II.6

      KindredID: F8

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+648T>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant;transition; splice_site_variant

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

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

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

      PatientID: II.1

      KindredID: 3

      Case: M, 0Y4M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

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

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

      CasePresentingHPOs: HP:0001901 (Polycythemia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.340+770T>C

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: intron_variant

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

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

    1. 24FVHLVHL p.Tyr152IleNRNRCarotid bodyNegativeNoNo

      PatientID: 24

      KindredID: 24

      Case: F, 24Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Negative family history.

      CasePresentingHPOs: HP:0002668 (paraganglioma)

      CaseHPOFreeText: a carotid body (paraganglioma) was reported with no other details.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.T152I (c.455C>T)

      CaseProblemVariantFreeText: Variant is written in paper under p.Tyr152Ile. This is incorrect however is paired to a paper where this variant it described (PMID: 18031321) referencing Thr152Ile, so this was deduced.

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName:T152I (c.455C>T)

      MultipleGeneVariants: N/A

    2. 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. variants of VHL in 18 probands

      PatientID: 14

      KindredID: 10

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family information provided.

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant, transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. PatientID: 37

      KindredID: 37

      Case: M, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: Unilateral benign adrenal pheochromocytoma that was operated on at age 26.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 32179488

      SupplementalData: N/A

      Variant: p.L63P (c.188T>C)

      LegacyVariant: L63P (c.401T>C)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant reported as L63P (c.401T>C), legacy nomenclature (AF010238.1), and was mapped to p.Leu63Pro (c.188T>C) in accordance with reference sequence NM_000551.3.

      MutationType: missense_variant;transition

      CivicName: L63P (c.188T>C)

      MultipleGeneVariants: N/A

    1. c.99_100InsA*

      PatientID: None (II)

      KindredID: 7

      Case: Sex and Ethnicity unknown; Age <18Y0M

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 16572651

      SupplementalData: N/A

      Variant: p.G34Rfs*98 (c.99_100insA)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: G34Rfs (c.99_100insA)

      MultipleGeneVariants: N/A

    1. Table 1

      PatientID: N/A

      KindredID: 16

      Case: F, Age Unknown, Brazilian

      DiseaseAssertion: VHL

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

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

      CaseHPOFreeText: Patient had VHL disease: CNS-HB, RCC, PCy (see table 1). Previously published 2018 paper (PMID:20567917) reports patient as an Brazilian 24Y female.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 20567917

      SupplementalData:  N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

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

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    2. Table 1)

      PatientID: N/A

      KindredID: 12

      Case: M, Age Unknown, Indian

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0002666; HP:0010797; HP:0001737; HP:0005584 (Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

      CaseHPOFreeText: Patient had CNS-HB, RCC, Unilateral PH, PCy (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 39Y male

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29124493

      SupplementalData:  N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    1. We observed 10 different intragenic mutations in 10/15 (66.7%) patients: five missense mutations

      PatientID: 12

      KindredID: 12

      Case: M, 48Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: None

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L163P (c.488T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVar: 2231 https://www.ncbi.nlm.nih.gov/clinvar/variation/2231/

      CAID: CA020423 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L163P (c.488T>C)

      MultipleGeneVariants: N/A

    1. S3135F?? ?-- - -c.214 T[Cp.S72P

      PatientID:1

      KindredID: S3

      Case: F, 35Y0M, Indian

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: multi-cystic pancreatic lesions and CNS hemangioblastoma

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S72P (c.214T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223163 https://www.ncbi.nlm.nih.gov/clinvar/variation/223163/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_transition

      CivicName: S72P(c.214T>C)

      MultipleGeneVariants: N/A

    1. c.548 C>Aap.S183X

      GroupID: 27A

      Case: Sex, Age, Ethnicity unknown

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S183* (c.548C>A)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

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

      PatientID: III-14

      KindredID: 1

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: asymptomatic

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

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Stated as carrier, however he is young (likely before the age of onset)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S168T (c.503G>C)

      MultipleGeneVariants: N/A

    1. PatientID: 262

      KindredID: 262

      Case: Sex Unknown, 54Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Positive family history for VHL.

      CasePresentingHPOs: HP:0009711, HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0001737, HP:0002666, HP:0006770, HP:0000107 (pancreatic cysts, pheochromocytoma, clear cell renal cell carcinoma, renal cyst)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2, S3.

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: CA70052558 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.583C%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    2. PatientID: 207

      KindredID: 207

      Case: Sex Unknown, 30Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history noted but details not specified.

      CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

      CaseHPOFreeText: CNS hemangioblastoma.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: F136S (c.407T>C)

      MultipleGeneVariants: N/A

    3. PatientID: 53

      KindredID: 53

      Case: Sex Unknown, 37Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family history noted but details not specified.

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

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

      Variant: p.V170G (c.509T>G)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170G (c.509T>G)

      MultipleGeneVariants: N/A

    4. PatientID: 4

      KindredID: 4

      Case: Sex Unknown, 26Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Table S1, S2 and S3

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: S80I (c.239G>T)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 1

      Case: M, 15Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: None

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

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

      CaseNotHPOs: N/A

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

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. 1M14PCC + PNETProgressive, inoperableNAS525325.7 (II)+−VHL (Exon:3)/p.(Arg167Trp

      PatientID: 1

      KindredID: 1

      Case: M, 14Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: No family information reported.

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

      CaseHPOFreeText: Patient was diagnosed with pheochromocytoma and pancreatic endocrine tumor.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense variant, transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. GroupID/ KindredID: VHL 51

      DiseaseAssertion: assumed VHL

      GroupSize: 6

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: German

      GroupAgeRange: N/A

      GroupInfo: 6 patients with the given mutation belonging to VHL family 51

      GroupPresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, Papillary cystadenoma of the epididymis)

      GroupHPOFreeText: CNS hemangioblastomas found in all 6 members of this cohort, and epididimal cystadenomas found in 4 members.

      GroupNotHPOs: GroupNotHPOFreeText: N/A

      GroupPreviousTesting: 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: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. PatientID: 37

      KindredID: 37

      Case: F, 26Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: Family positive for VHL. Father presented with CNS hemangioblastoma, pheochromocytoma and further unspecified phenotypes; was diagnosed with VHL Type 2A. Younger sister presented with pheochromocytoma; was diagnosed with VHL Type 2C. Genetic information was not provided for father and sister.

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

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

      CaseHPOFreeText: Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 2A.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: T157I (c.470C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 30

      KindredID: 30

      Case: F, 27Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: No family history of VHL.

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

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

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 19270817

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L128P (c.383T>C)

      MultipleGeneVariants: N/A

    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. GroupID: 4477

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Each group represents a family.

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

      GroupHPOFreeText: 1/2 members with pheochromocytoma, 2/2 members with CNS hemangioblastoma, 2/2 members with retinal angioma, 1/2 members with cysts. Diagnosed as a VHL Type 2B family. Localized pancreatic neuroendocrine tumor is also associated with this family but the number of family members affected is not specified.

      GroupNotHPOs: HP:0005584 (Renal cell carcinoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.712C>T

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: Variant reported as 712, C to T (Arg to Trp), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.499C>T, p.Arg167Trp (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    2. GroupID: 4783

      DiseaseAssertion: VHL

      GroupSize: 3

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Each group represents a family.

      GroupPresentingHPOs: HP:0002666; HP:0009711; HP:0030405 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic endocrine tumor)

      GroupHPOFreeText: 3/3 members with pheochromocytoma, 1/3 members with retinal angioma, Diagnosed as a VHL Type 2B family. Localized pancreatic neuroendocrine tumor is also associated with this family but the number of family members affected is not specified.

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

      GroupNotHPOFreeText: No CNS hemangioblastoma, RCC or cyst presentations.

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L128F (c.382C>T)

      LegacyVariant: c.595C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496060, https://www.ncbi.nlm.nih.gov/clinvar/variation/496060/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: Variant reported as 595, C to T (Leu to Phe), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.382C>T, p.Leu128Phe (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: L128F (c.382C>T)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 6

      Case: F, 53Y0M, Chinese

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

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

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

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

      CasePreviousTesting: N/A

      PreviouslyPublished: 29330336

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

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:W117G (c.349T>G)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 6

      Case: Sex Unknown, 44Y0M, Chinese

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29330336

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

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:W117G (c.349T>G)

      MultipleGeneVariants: N/A

    1. PatientID: none (daughter)

      KindredID: 2

      Case: F, 6Y0M, African/African American

      DiseaseAssertion: asymptomatic

      FamilyInfo: Her mother had the same mutation and bilateral adrenal pheochromocytoma and spinal hemangioblastoma. Her older brother was negative for the mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. GroupID: 11

      DiseaseAssertion: VHL

      GroupSize: 14

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Family of 14 VHL Type 1 affected individuals.

      GroupPresentingHPOs: HP:0002894; HP:0009711; HP:0010797; HP:0005584 (Neoplasm of the pancreas, Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)

      GroupHPOFreeText: CNS hemangioblastoma (7/14 affected members), renal carcinoma (1/14 affected members) and retinal angioma (2/14 affected members) and pancreatic cystadenoma (number of affected individuals not specified).

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.V130F (c.388G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant;transversion

      CivicName: V130F (c.388G>T)

      MultipleGeneVariants: N/A

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

      PatientID: IV:6

      KindredID: 1

      Case: F, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

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

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName:P25L (c.74C>T)

      MultipleGeneVariants: N/A

    1. VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations.

      PatientID: None

      KindredID: 107

      Case: Age, sex ethnicity unknown

      DiseaseAssertion: unknown; paper focused only on pheochromocytoma

      FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 107

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Unknown

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: No presence of phaeochromocytoma in family

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.N141Mfs*18 (c.421delA)

      CaseProblemVariantFreeText: NM_000551.3:c.421delA automapps to NM_000551.3:c.422delA

      LegacyVariant: FS (c.634delA)

      ClinVarID: N/A

      CAID: CA432421876 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.421delA

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: N141fs (c.422del)

      MultipleGeneVariants: N/A

    1. PatientID: V-29

      KindredID: 2

      Case: F, Age Unknown, German

      DiseaseAssertion: VHL

      FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7759077

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    2. PatientID: VI-2

      KindredID: 2

      Case: F, Age Unknown, German

      DiseaseAssertion: VHL (Asymptomatic)

      FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7759077

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    3. PatientID: V-35

      KindredID: 2

      Case: F, Age Unknown, German

      DiseaseAssertion: VHL

      FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7759077

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. nt 768, C to G, Tyr to stop, exon 3

      PatientID: 16

      KindredID: 6006

      Case: F, 24Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: She presented with one pathologic pancreatic endocrine tumour.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.Y185* (c.768C>G)

      CaseProblemVariantFreeText: N/A

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

      CAID: CA357075 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.555C%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    2. 3841Mnt 713 G to A, Arg to GlnR, 15960

      PatientID: 38

      KindredID: 5960

      Case: M, 41Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Another member of his family (patient 39) has the same VHL mutation and presents with one pathologic pancreatic endocrine tumour.

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: He presented with one radiologic pancreatic endocrine tumour.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.R167Q (c.713G>A)

      CaseProblemVariantFreeText: N/A

      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)

      MultipleGeneVariants: N/A

    3. 3627Fnt 712 C to T, Arg to TrpP, 36015

      PatientID: 36

      KindredID: 6015

      Case: F, 27Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: She presented with three pathologic pancreatic endocrine tumours.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. We observed 38-year-old hemodialyzed male patient diagnosed with von Hippel-Lindau disease in 2008 who was admitted to the Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia in Katowice with significant anemia, increased number of leukocytes, pneumonia and with suspected endocarditis.In June 2007 the patient underwent right nephrectomy for renal cell carcinoma and then in October 2007 he had surgery to remove a tumor from his brainstem (medulla oblongata) at the level of the posterior portion of the foramen magnum. Histological examination found hemangioblastoma which might have occurred as a feature of VHL disease.In 2008 the Department of Genetics and Pathology, Pomeranian Medical University in Szczecin detected a constitutional mutation 407 C/T (F136S) within the VHL gene. Study of the patient’s family history showed that his father, uncle and grandmother were diagnosed with renal cell cancer. The patient underwent annual screening program in order to identify cancer manifestations early.In October 2010, he was diagnosed with a solitary kidney tumor and qualified for surgical treatment. Histological examinations showed the tumor to be renal cell carcinoma. Postoperative course was complicated by massive hematuria leading to urgent nephrectomy resulting in chronic hemodialysis.In March 2011, he was diagnosed with dilated cardiomyopathy and complex valves defect. In May 2011, severe central sleep apnea was determined.In July 2011, patient was admitted to the hospital again. Blood tests showed anemia (HGB = 5, 6 g/dl), leukocytosis (WBC = 13×109/l) and moderate thrombocytopenia ( PLT = 72×109/l). There was no peripheral blood smear done.Gastroscopy revealed erosive gastritis. He required blood transfusion during the hospitalization. Following tests reported increasing number of white blood cells (up to 55×109/l) and reducing number of plates despite use of intravenous corticosteroids. A preliminary diagnosis was: infective endocarditis, pneumonia, erosive gastritis and duodenitis accompanied by anemia, leukocytosis and thrombocytopenia.The patient was then transferred to the Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice. Physical examination revealed a heart murmur and splenomegaly. Blood test showed persistent anemia, decreased plateled count and hyperleukocytosis. A peripheral blood smear determined the presence of blasts.Ultrasound imaging of the abdomen revealed enlarged spleen (14.6x9.9 cm). Bone marrow aspirate confirmed the findings of blood smear and showed the presence more than 50% of myelomonoblastic cells. The flow cytometric immunophenotyping report indicated the malignant cells were positive for HLA-DR, MPO, CD13, CD15, CD33, CD116 and cytogenetic analysis showed the inv (16) (p13;q22). Molecular analysis of bone marrow cells using RT-PCR identified a CBFB-MYH11 fusion protein.Low cytogenetic risk patient was treated with individualized induction therapy DA: daunorubicin (60 mg/m2 on days 1–3) and cytosine arabinoside (200 mg/m2 on days 1–5). Hemodiadialyzotherapy was continued. His chemiotherapy- induced bone marrow aplasia with granulocytopenia was complicated by pneumonia.The patient achieved a complete hematologic remission in peripheral blood, but not molecular remission after induction chemotherapy (positive RT-PCR assays for oncogene CBFB-MYH11). The Patient then received consolidation treatment with HAM (mitoxantrone 10 mg/m2 on days 1–2 and cytosine arabinoside 1500 mg/m2 on days 1–5). During the period of profound aplasia an additional hemodialysis due to hyperkalemia was required. Prolonged bone marrow aplasia resulted in severe interstitial pneumonia and septicemia. Despite intensive therapeutic measures the patient died from respiratory failure.The autopsy revealed a pulmonary edema, massive hyperemia of the left lower lobe with pneumonia confluens.

      PatientID: 1

      KindredID: 1

      Case: M, 38Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: His father, uncle and grandmother were diagnosed with renal cell cancer but no genetic data is available.

      CasePresentingHPOs: HP:0001903; HP:0002090; HP:0005584; HP:0010797; HP:0000790; HP:0001644; HP:0010535; HP:0001654; HP:0005263; HP:0001873; HP:0001974; HP:0006689; HP:0033117; HP:0030148; HP:0001744; HP:0006515; HP:0100806; HP:0100598; HP:0100598; HP:0004930; HP:0004808 (Anemia, Pneumonia, Renal cell carcinoma, Hemangioblastoma, Hematuria, Dilated cardiomyopathy, Sleep apnea, Abnormal heart valve morphology, Gastritis, Thrombocytopenia, Leukocytosis, Bacterial endocarditis, Duodenitis, Heart murmur, Splenomegaly, Interstitial pneumonitis, Sepsis, Pulmonary edema, Abnormality of the pulmonary vasculature, Acute myeloid leukemia)

      CaseHPOFreeText: 38-year-old male patient diagnosed with von Hippel-Lindau disease in 2008 admitted with significant anemia, increased number of leukocytes, pneumonia and with suspected endocarditis. In June 2007 the patient underwent right nephrectomy for RCC and then in October 2007 he had surgery to remove a hemangioblastoma from his brainstem (medulla oblongata). In October 2010, he was diagnosed with a solitary kidney tumor (histologically confirmed RCC). Postoperative course was complicated by massive hematuria leading to urgent nephrectomy resulting in chronic hemodialysis. In March 2011, he was diagnosed with dilated cardiomyopathy and complex valves defect. In May 2011, severe central sleep apnea was determined. In July 2011, anemia, leukocytosis and moderate thrombocytopenia were determined. Gastroscopy revealed erosive gastritis. A preliminary diagnosis was made of infective endocarditis, pneumonia and duodenitis. Physical examination revealed a heart murmur and splenomegaly. Blood test showed persistent anemia, decreased platelet count and hyperleukocytosis. Ultrasound imaging of the abdomen revealed enlarged spleen. Prolonged bone marrow aplasia resulted in severe interstitial pneumonia and septicemia. The patient died from respiratory failure. The autopsy revealed a pulmonary edema, massive hyperemia of the left lower lobe with pneumonia confluens.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: Authors declare variant as: “407 C/T (F136S)”.

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: F136S (c.407T>C)

      MultipleGeneVariants: N/A

    1. PatientID: None (proband’s father)

      KindredID: 2

      Case: M, Age Unknown, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: His daughter (25Y0M; proband), son, and 8-year-old grandson have also been diagnosed with VHL. His other infant grandson also tested positive for the VHL mutation (c.499C>T).

      CasePresentingHPOs: unknown

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: V266

      KindredID: V266

      Case: Sex Unknown, Age Unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Diagnosed with VHL Type 1.

      CaseNotHPOs: HP:0002666 (Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.W88S (c.263G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2220, https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W88S (c.263G>C)

      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: 16

      KindredID: C

      Case: Sex Unknown, 54Y0M, 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:0000107 (renal cyst)

      CaseHPOFreeText: Patient had renal cysts. They however appeared absent of clinical manifestations of VHL disease prior to clinical and imaging scrutiny.

      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: 26

      KindredID: N/A

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S6 describes 3 patients with small insertions, including this patient.

      Variant: p.R69Afs*63 (c.204dup)

      LegacyVariant: c.417insG

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA913189244

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant, duplication

      CivicName: R69Afs*63 (c.204_205insG)

      MultipleGeneVariants: N/A

    1. VHL3c.455C>Tp.Thr152Ile1LCBc

      PatientID: N/A

      KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: paraganglioma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002668 (paraganglioma)

      CaseHPOFreeText: Paraganglioma of the head and neck region (HNPGL): Left carotid body; nonsecreting paraganglioma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.T152I (c.455C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: T152I (c.455C>T)

      MultipleGeneVariants: N/A

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

      PatientID: 18

      KindredID: 18

      Case: M, 34Y0M, Asian Indian

      DiseaseAssertion: pheochromocytoma

      FamilyInfo:  None - Apparently sporadic

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: bilateral pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. 1

      PatientID: 1

      KindredID: 1

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: No family history

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Bilateral Pheochromocytoma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: no other endocrine tumours

      CasePreviousTesting: SDHB, SDHD, SDHC, RET

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y156C (c.467A>G)

      LegacyVariant: N/A

      ClinVar: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

      CAID: CA020394 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020394

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y156C(c.467A>G)

      MultipleGeneVariants: N/A

    1. PatientID: III-7

      KindredID: 1

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

      DiseaseAssertion: VHL

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

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

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

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: Lacked evidence of any pheos.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117C (c.351G>T)

      MultipleGeneVariants: N/A

    1. 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. PatientID: VI-13

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma, Paraganglioma, Retinal capillary hemangioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    2. PatientID: V-5

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    1. Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients (Table 1).

      PatientID: 14

      KindredID: 14

      Case: F, 56Y0M, Ethnicity unknown

      DiseaseAssertion: pancreatic endocrine tumor

      FamilyInfo: None

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

      CaseHPOFreeText: See Table 1 for more information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 2222 https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: CA020277 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.334T%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

    1. 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

  2. Oct 2026
    1. D3

      Case#: Patient D3, Druze religious group, located in lower Galilee.

      DiseaseAssertion: MPS-H

      FamilyInfo: Parents were heterozygous for the same mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 7

      Case#: Patient No. 7 (Table 1), Black race, male, 1.71 years (age at time of gene therapy), 80 IQ score, 1.73 years since gene therapy (1.5 years since latest visit)

      DiseaseAssertion: MPS-IH

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: Yes

      Variant1: c.923_926delTGCC (p.L308HfsX8)

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: c.923_926delTGCC (p.L308HfsX8)

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. The impact of the substitutions in exon 3’s last nucleotide (position c.550) on splicing was previously functionally evaluated using RNA analysis and was established as pathogenic [75]. In the same splice site, we detected a novel variant, c.550 + 3A > C, in a patient P02201 and as the variant had not been previously reported, we tried to functionally evaluate it. Unfortunately, none of the patient’s family members were available for testing. The variant potentially affecting the donor splice site (5'ss) of exon 3 was analyzed in silico by MaxEnt Score [76], and the ratio between mutated and wild-type 5'ss sequence was 0.41—a number suggesting a substantial effect on splicing. According to Le Guédard-Méreuze et al. [77], substitution + 3A > C is prone to cause a splicing defect even if the donor splice site does not contain any further nucleotide changes. We performed minigene analysis (detailed procedure described in Supplement Methods) to confirm the deleterious effect on splicing and it showed aberrant splicing in nearly 100% of mutated minigene construct transcripts (Fig. 3).Fig. 3Minigene splicing analysis of a novel variant c.550 + 3A > C. The wild-type and mutant genomic fragments of SERPING1 comprising exon 3 and flanking upstream (229 bp) and downstream (255 bp) intron sequences, were cloned into pET01 vector and HepG2 cells were transfected with these minigenes. Capillary electrophoresis of RT-PCR products showed aberrant splicing in nearly 100% of mutated minigene construct transcripts. Several different aberrant transcripts were detected. The most abundant was intron 3 retention followed by exon 3 skipping. Transcripts using cryptic donor splice sites − 10 and + 27 were found in the mutant minigene analysis, whereas they were not detected in the wild type at all. a Minigene analysis results: column A shows transcript proportions resulting from control minigene construct representing c.550 + 3A; column C shows transcript proportions resulting from minigene construct representing c.550 + 3C. b Scheme of the transcripts detected in the minigene analysis. c Scheme of the pET minigene construct. Cryptic splice sites found in the analysis and their exact sequences are displayed. MaxEnt Score values (MES) are specified beneath each splice siteFull size imageVariant c.686-7C > G was detected in a mother and her daughter (P03001-P03002), both affected with HAE symptoms. This variant had been described before [7], but its impact had not been yet fully evaluated. Therefore, we extracted RNA from both patients’ blood and analyzed samples by RT-PCR and fragment analysis (Supplementary Methods), which showed complete impairment caused by the variant (Fig. 4).Fig. 4mRNA analysis of patients carrying variant c.686-7C > G. Capillary electrophoresis was performed on PCR products amplified by primers annealing to exons 4 and 7. a Healthy control shows only one wild type peak. b Both patient sample results show 2 peaks—reference transcript peak and a peak corresponding to a 6 bp longer transcript using a de novo created acceptor splice site. Aberrant and normal transcript proportion was roughly equal, which corresponds to complete impairment caused by the variant. The variant preserves a reading frame and leads to incorporation of additional two amino acids (proline-alanine) into the polypeptide chain

      550+3A>C: Minigene analysis showed aberrant splicing in nearly 100% of mutated minigene construct transcripts, confirmed exon 3 splicing disruption

      686-7C>G: RT-PCR and fragment analysis. Both patient sample results show 2 peaks (WT shows only 1)—reference transcript peak and a peak corresponding to a 6 bp longer transcript using a de novo created acceptor splice site. Aberrant and normal transcript proportion was roughly equal, which corresponds to complete impairment caused by the variant. The variant preserves a reading frame and leads to incorporation of additional two amino acids (proline-alanine) into the polypeptide chain

      Variants: c.550+3A>C; c.686-7C>G

      CAIDs: CA2573332696;

    1. c.496_506del11 (p.Val166Serfs*4) in seven individuals, belonging to two pedigrees.

      PatientID: 82

      KindredID: 82

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29437867 (likely family 17 - see here for more info)

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

      Variant: p.V166Sfs*4 (c.496_506del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223229 https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_2_frameshift_variant

      CivicName: V166Sfs*4 (c.496_506del)

      MultipleGeneVariants: N/A

    1. Patient 1 The first patient had no familial history of VHL disease and was 21 years old when he experienced a sudden right hearing loss. The resulting cophosis was irreversible. The radiological work-up revealed an osteolytic mass of the right temporal bone of heterogeneous signal on both T1- and T2-weighted images (Fig. 1), consistent with the diagnosis of endolymphatic sac tumor. The tumor invaded the otic capsule and the petrous apex but did not extend in the cerebellopontine angle. Its mean tumor diameter (MTD) at diagnosis was approximately 2.6 cm (formula—MTD = (length×width×height)1/3MTD = (length×width×height)1/3 {\hbox{MTD = }}{\left( {{\hbox{length}} \times {\hbox{width}} \times {\hbox{height}}} \right)^{{1/3}}} ) [16]. The rest of the neurological exam was normal and a conservative management was decided. During follow-up, the patient suffered from other manifestations of VHL disease: retinal and central nervous system hemangioblastomas, pheochromocytoma, renal tumors, and pancreatic cysts. The germline mutation of the VHL gene was also identified (c.337C>T, p.Arg113X). After 20 years of radiological surveillance, the size of his endolymphatic sac tumor remains stable (Fig. 2). Apart from his deafness, the patient does not suffer from any vestibular symptoms and his facial function is normal (House and Brackmann grade I).

      PatientID: 1

      KindredID: 1

      Case: M, 41Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: No family history of VHL disease.

      CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0002666; HP:0009726; HP:0001737 (endolymphatic sac tumor, retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal neoplasm, pancreatic cysts)

      CaseHPOFreeText: patient was 21 years old when he experienced a sudden right hearing loss (cophosis). During a follow-up, the patient suffered from other manifestations of VHL disease mentioned above.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R113* (c.337C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

      CivicName: R113*(c.337C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 9

      KindredID: 9

      Case: F, 16Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: No family history of VHL.

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

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseHPOFreeText: Diagnosed with VHL Type 1.

      CaseNotHPOs: HP:0002666; HP:0005584; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: E70K (c.208G>A)

      MultipleGeneVariants: N/A

    1. IV 10 21 2 pheo (12 years) 1 retinal hb (10 years) M c.278G > A (p.Gly93Asp)

      PatientID: IV

      KindredID: 3

      Case: Sex Unknown, 21Y0M, Danish

      DiseaseAssertion: VHL

      FamilyInfo: 3 other family members presented with his VHL mutation. Patient 3-I was asymptomatic. Patients 3-II and 3-III both presented with pheochromocytoma at 15Y.

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

      CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with pheochromocytoma at 12Y and retinal hemangioblastoma at 10Y. Age at the end of study: 21Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: G93D (c.278G>A)

      MultipleGeneVariants: N/A

    1. 18 c.509T>A p.Val170Asp p.V170D Familial VHL

      GroupID/ KindredID: 18

      DiseaseAssertion: VHL

      GroupSize: 14

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

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

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

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

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: V170D (c.509T>A)

      MultipleGeneVariants: N/A

    1. c.99_100InsA*

      PatientID: None (XIII)

      KindredID: 7

      Case: Sex and Ethnicity unknown; Age >18Y0M

      DiseaseAssertion: asymptomatic

      FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 16572651

      SupplementalData: N/A

      Variant: p.G34Rfs*98 (c.99_100insA)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

      CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: plus_1_frameshift_variant

      CivicName: G34Rfs (c.99_100insA)

      MultipleGeneVariants: N/A

    1. PatientID: 9

      KindredID: 2

      Case: F, 29Y0M, African/African American

      DiseaseAssertion: VHL

      FamilyInfo: She was 23 weeks pregnant at the time of a pheochromocytoma resection. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother (although no testing conducted) and daughter were said to be investigated further and monitored long-term.

      CasePresentingHPOs: HP:0006748; HP:0009713 (adrenal pheochromocytoma; spinal hemangioblastoma)

      CaseHPOFreeText: At the time, the patient was 23 weeks pregnant and had bilateral adrenal phaeochromocytomas removed. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. F10, II.1c.429C>T/c.429C>TVHL p.Asp143Asp/VHL p.Asp143Asp2002/4.5 yF22.564-77.412.6264Erythrocytosis, splenomegalyβ thalassemia

      PatientID: II.1

      KindredID: F10

      Case: M, 4Y6M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: This patient’s asymptomatic patients were both found to be carriers of the D143= (c.429C>T) germline variant in VHL. Their other child (II.2) also carried the gene. The current patient was the only one who was homozygous for the variant.

      CasePresentingHPOs: HP:0001901; HP:0001744 (Polycythemia, Splenomegaly)

      CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and splenomegaly at 4.5 years old (DOB: 2002).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D143= (c.429C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 416990, https://www.ncbi.nlm.nih.gov/clinvar/variation/416990/

      CAID: N/A

      gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/3-10188286-C-T?dataset=gnomad_r2_1

      VariantEvidence: Variant is present in allele 1 and 2 (i.e. homozygous).

      MutationType: missense_variant;transition; synonymous_variant

      CivicName: D143= (c.429C>T)

      MultipleGeneVariants: Germline, Beta Thalassemia

    2. F4, II.1c.598C>T/c.340+694_711dupVHL p.Arg200Trp/X1 p.Trp159X?1990/7 yM20.6648.2549.9Erythrocytosis, deep vein thrombosis, intracerebral hemorrhageFV Leiden

      PatientID: II.1

      KindredID: F4

      Case: M, 7Y0M, Ethnicity Unknown

      DiseaseAssertion: Polycythemia

      FamilyInfo: Variant c.340+694_340+711dup is inherited from mother (genetically confirmed) and variant R200W (c.598C>T) is assumed to be inherited from father.

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

      CasePresentingHPOs: HP:0001901; HP:0002625; HP:0001342 (Polycythemia, Deep venous thrombosis, Cerebral hemorrhage)

      CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia), deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990).

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: Variants are heterozygous.

      MutationType: missense_variant;transition

      CivicName: R200W (c.598C>T) and c.340+694_340+711dup

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

      MultipleGeneVariants: Germline, Factor V Leiden

    1. PatientID: III-40

      KindredID: 1

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

      DiseaseAssertion: asymptomatic

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

      CasePresentingHPOs: None

      CaseHPOFreeText: VHL found by genetic testing not clinical findings.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.688delA

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: E160fs (c.477del)

      MultipleGeneVariants: N/A

    1. MSL128F1 (5.6)1 (3.8)

      GroupID: 8

      Case: Age, Sex, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: 1 individual belonging to 1 family was mentioned with this VHL mutation. No other family info was provided.

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: Other manifestations aside from pheochromocytoma are possible; but not specified.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L128F (c.381_382delinsTT)

      CaseProblemVariantFreeText: Paper called "L" Lysine but it matches to Leucine in all 3 cases. Likely an error in word choice by authors.

      LegacyVariant: N/A

      ClinVarID: 223203 https://www.ncbi.nlm.nih.gov/clinvar/variation/223203

      CAID: CA357088 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.381_382delinsTT

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: delins

      CivicName: L128F (c.381_382delinsTT)

      MultipleGeneVariants: N/A

    1. PatientID: 162

      KindredID: 62

      Case: F, 14Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The patient's mother presented with a CNS hemangioblastoma at age 28, and a renal cell carcinoma, multiple pancreatic cysts/tumors, and a pheochromocytoma at age 41.

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

      CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 14.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

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

      MultipleGeneVariants: N/A

    2. PatientID: 124

      KindredID: 44

      Case: M, Age 24Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 18, renal cell carcinoma and multiple pancreatic cysts/tumors at 24.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

      Variant: p.W117S (c.350G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753671; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: W117S (c.350G>C)

      MultipleGeneVariants: N/A

    3. PatientID: 194

      KindredID: 74

      Case: F, 36Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband, patient 193, has a mother (patient 194) who was also found to have the same germline mutation. The proband had a CNS hemangioblastoma at age 16.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: The patient presented with a pheochromocytoma at age 36.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    4. PatientID: 146

      KindredID: 52

      Case: M, Age Unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The proband's nephew (son of sister 2) was asymptomatic at the time of assessment.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

      Variant: c.464-1G>C

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

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

      MultipleGeneVariants: N/A

    5. PatientID: 184

      KindredID: 71

      Case: M, Age 27Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband's mother (patient 185) was confirmed with the mutation but was asymptomatic at the time of testing. The proband (patient 184) presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

      CaseHPOFreeText: The proband presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

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

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

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. Table 1

      PatientID: N/A

      KindredID: 13

      Case: F, Age Unknown, Indian

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Patient had Unilateral PH (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 45Y female.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 29124493

      SupplementalData:  N/A

      Variant: p.F76del (c.227_229del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229del)

      MultipleGeneVariants: N/A

    2. Table 1

      PatientID: N/A

      KindredID: 9

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patient had VHL disease.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 28388566

      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/A

    1. 1 Italy c.358A>G p.Arg120Gly

      GroupID: 15

      Case: Sex unknown, Age unknown, Italian

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R120G (c.358A>G)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 223199 https://www.ncbi.nlm.nih.gov/clinvar/variation/223199/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R120G (c.358A>G)

      MultipleGeneVariants: N/A

    2. 2 France c.486C>G p.Cys162Trp

      GroupID: 26

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 2 registrants from France were grouped in this study via the mutation of c.486C>G

      GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      GroupHPOFreeText: N/A

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: C162W (c.486C>G)

      MultipleGeneVariants: N/A

    3. 2 France c.583C>T p.Gln195*

      GroupID: 35

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: Two registrants from France both have the same mutation of c.583C>T.

      GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

      GroupHPOFreeText: N/A

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. PMID: 7977367

      KindredID: 17

      DiseaseAssertion: VHL

      GroupSize: Unknown

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This is a family belonging to prefigure No. 17. They are described as ‘VHL-affected’.

      GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

      GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.76delF (c.227_229delTTC)

      LegacyVariant: p.147delF (c.437_439del3)

      CaseProblemVariantFreeText: c.224_226 automaps to NM_000551.3:c.227_229delTCT (updated; verified)

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence:N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229delTCT)

      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

    1. 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. 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. GroupID: 16

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: N/A

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

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.688delA

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: deletion; minus_1_frameshift_variant

      CivicName: E160fs (c.477del)

      MultipleGeneVariants: N/A

    1. 4335Fnt 454 C to T, Pro to SerP, 45959nt 775 C to G, Leu to Val

      PatientID: 43

      KindredID: 5959

      Case: F, 35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L188V (c.562C>G)

      LegacyVariant: p.L188V (c.775C>G)

      CaseProblemVariantFreeText: N/A

      ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

      CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

      gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: L188V (c.562C>G)

      MultipleGeneVariants: Germline, VHL, c.241C>T (p.Prp81Ser)

    2. nt 695 G to A, Arg to Gln

      PatientID: 28

      KindredID: 6014

      Case: F, 43Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

      CaseHPOFreeText: She presented with one radiologic pancreatic endocrine tumour.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. The missense mutation p.Arg167Gln in VHL exon 3 was detected in an index female (patient #2) and her mother

      PatientID: None

      KindredID: 2

      Case: F, Age unknown, Bulgarian

      DiseaseAssertion: VHL

      FamilyInfo: Patient has a daughter (PatientID: 1) with bilateral pheo and retinal hemangioma as well.

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

      CaseHPOFreeText: bilateral pheochromocytoma

      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. Meanwhile, it was also found that the guanine replaced the 559th cytosine on one patient and two carriers from the third family, which made the 116th leucine replaced by valine.

      PatientID: III-7

      KindredID: 3

      Case: F, Age Unknown, Chinese

      DiseaseAssertion: asymptomatic

      FamilyInfo: The transition mutation was found and confirmed in this patient’s mother (II-3) and 2 carriers, her, and her first-cousin once removed (III-7, IV-2). 5 additional members had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Stated as carrier, however she is young (likely before the age of onset)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.L116V (c.346C>G)

      LegacyVariant: p.L116V (c.559C>G)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: L116V (c.346C>G)

      MultipleGeneVariants: N/A

    1. 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

    1. 14F/11ASB/L PCC+sPGLVHL3c.500G>Ap.(Arg167Gln)Substitution (missense)Disease causingProbably damaging score 1.000DamagingNRNR

      PatientID: 14

      KindredID: 14

      Case: F, 11Y0M, Asian Indian

      DiseaseAssertion: assumed VHL

      FamilyInfo: None - Apparently sporadic

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

      CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic PGL

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

    1. three familial cases

      PatientID: 5

      KindredID: C

      Case: M, Age Unknown, Japanese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: This mutation was found in a family of 10 individuals; six were found to carry the mutation NM_000551.3:c.464-1G>T the patient carried, and three presented with symptoms. They were identified with hemangioblastomas of the central nervous system and retinal angiomas. The eldest patient also had renal cell carcinoma (patient C-1).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The paper states that this patient was not yet symptomatic, suggesting they may be too young to show symptoms yet.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: (c.464-1G>T)

      LegacyVariant: (c.677-1G>T)

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: splice_site_variant

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

      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

    1. PatientID: 1 (Proband)

      KindredID: 17

      Case: F, 3Y0M, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: 6 members of this family tested positive for the c.496_506del germline variant of the VHL gene. ID 4 presented with CNS hemangioblastoma, retinal angioma and renal and pancreatic abnormalities. ID 25 and 8 were asymptomatic.ID 22 presented with CNS hemangioblastoma. ID 5 presented with retinal angioma. 2 members were assumed to have the variant but were not genetically confirmed (ID 20 and ID 11). ID 11 and 20 presented with CNS hemangioblastoma.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Abnormality of the kidney, Abnormality of the pancreas, Retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table 1.

      Variant: p.V166Sfs*4 (c.496_506del)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223229, https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: It is unclear from the publication if this variant is reported according to legacy (AF010238.1) or NM_000551.3 reference sequence. Clinical notes from the case confirm the reference sequence to be NM_000551.3.

      MutationType: deletion; minus_2_frameshift_variant

      CivicName: V166SFS*4 (c.496_506del)

      MultipleGeneVariants: N/A

    1. A149S (34) 4 

      GroupID: None

      DiseaseAssertion: VHL

      GroupSize: 4

      GroupNumberMales:N/A

      GroupNumberFemales:N/A

      GroupEthnicity: N/A

      GroupAgeRange: ≥12

      GroupInfo: The four patients were grouped by mutation.

      GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

      GroupHPOFreeText: N/A

      GroupNotHPOs:N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.A149S (c.445G>T)

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID:127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: A149S (c.445G>T)

      MultipleGeneVariants: N/A

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

      PatientID: BII2

      KindredID: B

      Case: M, 40Y0M, Serbian

      DiseaseAssertion: VHL

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

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense variant; transition

      CivicName: V84M (c.250G>A)

      MultipleGeneVariants: N/A

    1. PatientID: 5

      KindredID: 2

      Case: F, 20Y0M, Indian

      DiseaseAssertion: VHL

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

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

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: Bilateral pheochromocytoma.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. 473T→C Ts Exon 3 158 CTG L L158P

      GroupID: 42

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A - only 1 patient reported here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: Other manifestations are possibly but not clearly reported

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: L158P (c.473T>C)

      MultipleGeneVariants: N/A

    2. 571delC Fs Exon 3 191 CAC H Stop201

      GroupID: 52

      Case: Age unknown, Sex unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: None - one member documented here

      CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

      CaseHPOFreeText: other manifestations are not clearly stated.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: Possibly published in PMID:15300849

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: minus_1_frameshift_variant

      CivicName: H191FS (c.571delC)

      MultipleGeneVariants: N/A

    1. This mutation was inherited from the paternal allele

      PatientID: None (father)

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: Asymptomatic

      FamilyInfo: No significant family history.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant;transversion

      CivicName: V194G (c.581T>G)

      MultipleGeneVariants: N/A

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

      GroupID/ KindredID: 11BMS

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 11BMS. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.T152Hfs*22 (c.452_453insA)

      LegacyVariant: FS (c.665insA)

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA2573131771 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.452_453insA

      gnomAD: N/A

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

      MutationType: plus_1_frameshift_variant

      CivicName: T152fs (c.452_453insA)

      MultipleGeneVariants: N/A

    1. 16 different families

      PatientID: 2

      KindredID: 5

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.G93R (c.277G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant, transversion

      CivicName: G93R (c.277G>C)

      MultipleGeneVariants: N/A

    1. PatientID: VII-2

      KindredID: 1

      Case: M, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

      CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

      CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

      CaseNotHPOs: HP:0005584; HP:0002666; HP:0002668 (Renal cell carcinoma, Pheochromocytoma, Paraganglioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

      SupplementalData: N/A

      Variant: p.Y112H (c.334T>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y112H (c.334T>C)

      MultipleGeneVariants: N/A

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

      PatientID: IV-13

      GroupID/ KindredID: 6

      Case: Age unknown, M, Chinese

      DiseaseAssertion: asymptomatic

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

      CasePresentingHPOs: None

      CaseHPOFreeText: N/A

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

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

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. 2/M 10 Yes 63 271 Hypersensitive NI 376G>T/wt 

      PatientID: 2

      KindredID: 1

      Case: M, 10Y0M, Ukrainian

      DiseaseAssertion: Asymptomatic

      FamilyInfo: His sister (patient 1) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

      CasePresentingHPOs: HP:0001901 (polycythemia)

      CaseHPOFreeText: Patient had a hematocrit of 63%, erythropoietin level of 271 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: No tumor masses were detected by repeated CT scans of his abdomen or chest and by magnetic resonance imaging (MRI) of the head.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.D126Y(c.376G>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

      CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

      gnomAD: N/A

      VariantEvidence: Patient was heterozygous for the mutation.

      MutationType: missense_variant;transversion

      CivicName: D126Y(c.376G>T)

      MultipleGeneVariants: N/A

    1. F119 18 F left 3 23  2 VHL R64P VHL

      PatientID: F119

      KindredID: 1

      Case: F, 20Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: The patient had a pheochromocytoma in the left adrenal gland. It was measured to be 3 cm in size and 23 grams in weight.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R64P(c.191G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R64P(c.191G>C)

      MultipleGeneVariants: N/A

    1. PatientID: 10

      KindredID: 10

      Case: M, 26Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0009713 (spinal hemangioblastoma)

      CaseHPOFreeText: The patient had a spinal hemangioblastoma at the C4/C5 boundary. The patient showed an high-normal Hb values (18.6) which fits the polyglobulia disease criteria. After the spinal hemangioblastoma was removed, the Hb normalized.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: p.S65W(c.407C>G)

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName:S65W(c.194C>G)

      MultipleGeneVariants: N/A

    1. PatientID: N/A

      KindredID: 23530

      Case: Age unknown, Sex unknown, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Paper states familial VHL

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

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes (Specifically Supp. Table S2)

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: L89P (c.266T>C)

      MultipleGeneVariants: N/A

    1. VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations.

      PatientID: None

      KindredID: 134

      Case: Age, sex ethnicity unknown

      DiseaseAssertion: unknown; paper focused only on pheochromocytoma

      FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 134

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Unknown

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 32179488, 17024664

      SupplementalData: N/A

      Variant: p.F76del (c.227_229delTCT)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: p.F76del (c.440delTCT)

      ClinVarID: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion

      CivicName: F76del (c.227_229delTTC)

      MultipleGeneVariants: N/A

    1. V#1exon 3c.500G > Ap.R167QCNS-HB, renal carcinoma

      PatientID: 1

      KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Yes

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: Confocal staining shows the distribution of pVHL in the cell cytoplasm.

      MutationType: missense_variant; transition

      CivicName: R167Q (c.500G>A)

      MultipleGeneVariants: N/A

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

      PatientID: 7

      KindredID: 7

      Case: M, 14Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: None

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

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

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

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: N78S (c.233A>G)

      MultipleGeneVariants: N/A

    1. VHL-19c.500G > Ap.Arg167Gln[2]noA2MultipleBilateral––––

      PatientID: VHL-19

      KindredID: 19

      Case: Sex Unknown, Age Unknown, Italian

      DiseaseAssertion: VHL

      FamilyInfo: None.

      CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

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

      CaseHPOFreeText: Multiple hemangioblastoma of the CNS and spinal cord. Bilateral renal cell carcinoma.

      CaseNotHPOs: HP:0001737, HP:0002666, HP:0009711 (pancreatic cysts, pheochromocytoma, retinal capillary hemangioma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence:N/A

      MutationType: missense_variant;transition

      CivicName: R167Q (c.500 G >A)

      MultipleGeneVariants: N/A

    1. c.482 G>Aap.R161Q

      GroupID: 22A

      DiseaseAssertion: VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. 2 (100)

      GroupID: 37

      DiseaseAssertion: VHL

      GroupSize: 2

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

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

      GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      GroupProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: V155L (c.463G>C)

      MultipleGeneVariants: N/A

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

      PatientID: 4

      KindredID: 4

      Case: 16Y1M, sex unknown ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: None

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

      CaseHPOFreeText: spinal hemangioma was cervical.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: c.341-1G>A

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: splice_site_variant

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

      MultipleGeneVariants: N/A

    1. GroupID: 44

      DiseaseAssertion: VHL

      GroupSize: 5

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: French

      GroupAgeRange: N/A

      GroupInfo: 5 members of this family were found to have the germline c.226_228del variant of the VHL gene. Member 4975 presented with moderate renal disease (RCC), members 4978, 4977 and 4976 presented with mild renal disease and member 5283 had unknown renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

      GroupNotHPOs: N/A

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

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

      Variant: p.F76del (c.226_228del)

      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.226_228del

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: inframe_deletion; deletion

      CivicName: F76del (c.226_228del)

      MultipleGeneVariants: N/A

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

      PatientID: None

      KindredID: 1

      Case: M, 32Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

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

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

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

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

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

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    1. c.236G>C, p.R79P

      PatientID: II-1

      KindredID: Family B

      Case: M, 23Y0M, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: Family positive pedigree showing patient’s father with RCC and CNS hemangioblastoma; as well as 2 sisters with CNS/spinal and retinal hemangioblastomas

      CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioblastoma)

      CaseHPOFreeText: underwent surgery for multiple CNS hemangioblastomas at the age of 15, and at the same age multiple peripheral retinal hemangioblastomas were found in his right eye, which were treated successfully with laser photocoagulation and cryotherapy. At the age of 20, he developed a large peripheral retinal hemangioblastoma in his left eye, which was treated successfully with cryotherapy.

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

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.R79P (c.236G>C)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: N/A

      CAID: CA351749311 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.236G%3EC

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transversion

      CivicName: R79P (c.236G>C)

      MultipleGeneVariants: N/A

    1. PatientID: 8

      KindredID: 8

      Case: M,35Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: The patient had a meckel cave hemangioblastoma at age 28. The patient had a papillary edema and pituitary stalk hemangioblastoma at age 34. The patient died of VHL disease.

      CaseNotHPOs: N/A

      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. PatientID: 1

      KindredID: 1

      Case: M, 68Y0M, Ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: None.

      CasePresentingHPOs: HP:0002666; HP:0009711; HP:0000107 (pheochromocytoma, retinal capillary hemangioma, renal cyst)

      CaseHPOFreeText: Patient was found observed to have retinal angioma (retinal capillary hemangioma) and a right kidney cortex cyst (30mm). Patient's pheochromocytoma was found incidentally and he remained asymptomatic with steady weight.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET, SDHB, SDHC and SDHD

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P25L (c.74C>T)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: VHL23

      Case: M, 13Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: The patient had one malignant pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET/SDHB/SDHC/SDHD

      PreviouslyPublished: N/A

      SupplementalData: Table 1 of Supplementary

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

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

      MutationType: missense_variant;transition

      CivicName: L178P (c.533T>C)

      MultipleGeneVariants: N/A

    1. PatientID: 6 (tumour 8)

      KindredID: 7

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002666 (pheochromocytoma)

      CaseHPOFreeText: Patient had one benign pheochromocytoma.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: RET

      PreviouslyPublished: 7759077, 9681856

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: CA020246 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EC

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

      VariantEvidence: Refer to Table 1 for LOH information.

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. Case reportA 19-year-old woman was referred to our psychiatric inpatient service in June 2017, with the suspicion of AN. At the time of hospital admission, the patient's weight was 28 kg, her height was 1.55 m and her body mass index (BMI) was 11.6 kg/m2. The patient had had no menstrual cycle for at least 1 year. Over the previous 2 years, her food intake had progressively diminished, without an immediately apparent cause. The patient was hungry but felt satiated after ingesting only a small amount of food, and had difficulty swallowing.

      PatientID: N/A (case)

      KindredID: 1

      Case: F, 19Y0M, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: Non-consanguineous parental relationship; second child; no mention of VHL in the family.

      CasePresentingHPOs: HP:0010797; HP:0001713; HP:0002039; HP:0001824 (Hemangioblastoma; pancreatic cysts; anorexia; weight loss)

      CaseHPOFreeText: Healthy from birth, this patient was referred to a psychiatric inpatient at 19Y with the weight loss and weakness, and the suspicion on anorexia nervosa. AN was not met according to the DSM-5 or ICD-10 (despite anorexic tendencies). There were also no tendencies towards an eating disorder. Patient developed progressive gait abnormality, along with bilateral dysmetria. MRI revealed a massive lesion with vascular characteristics suggestive of a HB in the fourth ventricle causing hypertensive hydrocephalus. Abdominal CT scan revealed cystic lesions throughout the parenchymatous portion of the pancreas, suspected to be related to VHLs. Together, supported the diagnosis of VHL. The patient underwent surgery of the brain, and radiotherapy which proved to work in small degrees.

      CaseNotHPOs: HP:0002666 (pheochromocytoma)

      CaseNotHPOFreeText: All blood tests, urinalysis and chest X‑ray were unremarkable. She also had no pheochromocytoma.

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A

    1. PatientID: 6

      KindredID: 6

      Case: F, 29Y0M, Korean

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: 55 patients treated at Asan Medical Center in Korea treated between January 1995 and February 2013 clinically diagnosed with VHL disease and presenting with pancreatic lesions.

      CasePresentingHPOs: HP:0001737, HP:0030405 (pancreatic cysts, pancreatic endocrine tumor)

      CaseHPOFreeText: The patient presented with serous cystadenoma and pancreatic endocrine tumour at age 26. She was followed up 35.8 months later when her disease was reported to have progressed.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: P86S (c.256C>T)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 1

      Case: M, 11Y0M, Ethnicity unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: Familial/syndromic (FS) association

      CasePresentingHPOs:HP:0002666; HP:0009711 (Pheochromocytoma; retinal capillary hemangioma)

      CaseHPOFreeText: Benign bilateral pheochromocytoma and retinal angioma at age 11

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

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

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 6103

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

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

      CaseHPOFreeText: Diagnosed with CNS hemangioblastoma, pheochromocytoma, retinal angioma and VHL Type 2B.

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: c.712C>T

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: Variant reported as 712, C to T (Arg to Trp), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.499C>T, p.Arg167Trp (NM_000551.3).

      MutationType: missense_variant;transition

      CivicName: R167W (c.499C>T)

      MultipleGeneVariants: N/A

    1. VHL_3Frozenc.482G>Ap.Arg161GlnM37AdrenalPCCB

      PatientID: VHL_3 (tumor ID)

      KindredID: 3

      Case: M, 37Y0M, Ethnicity Unknown

      DiseaseAssertion: Adrenal pheochromocytoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

      CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 37Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

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

      PatientID: (mother)

      KindredID: 2

      Case: F, Age unknown, Chinese

      DiseaseAssertion: unknown

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

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

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

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

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

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: R161Q (c.482G>A)

      MultipleGeneVariants: N/A

    1. Proband's mother – 12

      PatientID: None

      KindredID: 1

      Case: F, 48Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: The patient’s aunt presented with Hodgkin’s lymphoma at 38Y and was deceased at 40Y. The patient’s father presented with liver cancer at 72Y and was deceased at 74Y. Additionally, the patient’s deceased grandfather had an unspecified cancer. The patient’s son presented with unilateral pheochromocytoma at 13Y. The patient’s daughter presented with pheochromocytoma at 12Y, and bilateral retinal hemangioblastoma, right adrenal pheochromocytoma, and islet cell neuroendocrine carcinoma of the pancreas with nodal metastasis at 20Y, and was found to carry the mutation the patient carried.

      CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, retinal hemangioblastoma)

      CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 12Y and retinal hemangioblastoma at 13Y.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

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

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_loss

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

      MultipleGeneVariants: N/A

    1. PatientID: V-14

      KindredID: 2

      Case: M, Age Unknown, German

      DiseaseAssertion: VHL

      FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

      CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 7759077

      SupplementalData: N/A

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

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

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

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: Y98H (c.292T>C)

      MultipleGeneVariants: N/A

    1. No abstract available

      PatientID: V-1

      KindredID: 1

      Case: M, 46Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: The patient’s grandmother and two uncles had died with cerebellar hemangioblastoma, although genetic testing was not performed. The patient’s father presented with cerebellar hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and serous cystadenoma at 68Y, adrenal pheochromocytoma at 73Y, and clear cell renal cell carcinoma metastasis in the thyroid at 74Y; he was found to carry the same mutation the patient carried. One of the patient’s sons, a 10Y male, was also found to carry the same mutation as the patient but was asymptomatic. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

      CasePresentingHPOs: HP:0009726; HP:0000107; HP:0001737 (Renal tumour, renal cyst, pancreatic cyst)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant: N/A

      ClinVarID: 193118, http://www.ncbi.nlm.nih.gov/clinvar/variation/193118

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transversion

      CivicName: R82P(c.245G>C)

      MultipleGeneVariants: N/A

    1. PatientID: None

      KindredID: 8

      Case: M, 8Y0M, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: His father had the same VHL mutation and presented with hemangioblastoma, clear cell renal cell carcinoma, and abnormality of the pancreas.

      CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0010797, HP:0006770, HP:0001732 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, hemangioblastoma, clear cell renal cell carcinoma, abnormality of the pancreas)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

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

      LegacyVariant:N/A

      CaseProblemVariantFreeText: N/A

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

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: stop_gained

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

      MultipleGeneVariants: N/A