KindredID: 27

GroupID: 27

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 27 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. No additional phenotypic information is listed for this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.F207S (c.620T>C)

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

PatientID: II-1

KindredID: 1

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

DiseaseAssertion: assumed VHL

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. None of her children or grand/great grand children were recorded with the VHL See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0002011; HP:0009711; HP:0000077 (Morphological central nervous system abnormality, retinal capillary hemangioma; Abnormality of the kidney)

CaseHPOFreeText: Patient mentioned to have CNS (including retinal angiomas) and renal involvement.

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

PatientID: III-9

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000541; HP:0002542; HP:0001737; HP:0000107; HP:0030405; HP:0001272; HP:0007366; HP:0010873; HP:0001251; HP:0001260; HP:0001310 (hemangioblastoma, Retinal capillar hemangioma, Retinal detachment, Olivopontocerebellar atrophy, Pancreatic cysts, Renal cyst, Pancreatic endocrine tumor, Cerebellar atrophy, Atrophy/Degeneration affecting the brainstem, Cervical spinal cord atrophy, Ataxia, Dysarthria, Dysmetria)

CaseHPOFreeText: diagnosed with VHL in her early teenage years. She had retinal involvement beginning at the age of 13 treated by cryotherapy and laser therapy (presumably for retinal angiomas); and retinal detachment at the age of 23 requiring eye surgery. She had cysts of the pancreas and kidney detected at 22 years. She has also carried the diagnosis of OPCA since the age of 26-28 (new onset slurred speech and illegible handwriting). Patient had multiple renal cysts without renal tumours, however a large infiltrative enhancing mass in the tail of the pancreas was suggestive of a neuroendocrine/islet cell carcinoma, and liver metastatic foci

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: SCA2 (an abnormal increase in CAG repeats in one allele of her ataxin-2 gene. This abnormal trinucleotide expansion is consistent with the diagnosis of spinocerebellar ataxia type 2)

PatientID: II-26

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0006770; HP:0009713; HP:0002031; HP:0003396; HP:0001649; HP:0001737; HP:0030424 (cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma, spinal hemangioblastoma, Abnormal esophagus morphology, Syringomyelia, Tachycardia, pancreatic cysts, epididymal cyst)

CaseHPOFreeText: CNS (including retinal angiomas) and renal involvement; with cerebellum hemangioblastoma found at age 34Y. An oesophageal abnormality that was treated with vagotomy at age 35Y. At age 44Y had bilateral clear cell renal cancer resulting in a right partial nephrectomy and left total nephrectomy. Same year had spinal surgery to treat a syrinx associated with a spinal cord haemangioblastoma, as well as cystic lesions in the pancreas (consistent with epididymal cystadenoma).

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

GroupID: 208

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.T105P (c.313A>C)

LegacyVariant: c.526A>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A

GroupID: 97

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.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: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 161

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: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

Variant: p.E186K (c.556G>A)

LegacyVariant: c.769G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 161403, https://www.ncbi.nlm.nih.gov/clinvar/variation/161403/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E186K (c.556G>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: C

Case: F, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Hemangioblastoma

FamilyInfo: Positive: The patient’s sister, one of two brothers, and mother each had the same germline mutation, although without any manifestations. As such, her family history was negative for kidney cancer, hemangioblastoma, or other features of VHL. See Fig. 3.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: In 2013, at 32Y, patient presented with a hemangioblastoma in her cerebellar region.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No other VHL- related tumors are present in this patient.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Immunohistochemistry was positive for Inhibin, and negative for RCC, GFAP, and OLIG2.

MutationType: missense_variant; transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: Somatic, VHL, c.188_188T>TG (p.Leu63fs*4)

GroupID/ KindredID: F42

Case: Sex unknown, 13Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents of clear cell carcinoma and renal cysts were found

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

CaseHPOFreeText: Age of onset is 13Y0M.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107 (pheochromocytoma, clear cell renal cell carcinoma, renal cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: g.8665A>G (splice-site)

CaseProblemVariantFreeText: Patient was reported with the g. (genomic) coding positions. The g.8665A>G variant worked out to correspond with p.P154P (c.462A>G). This also happens to be a synonymous variant, not a splice variant like the paper calls it.

ClinVarID: 411977 https://www.ncbi.nlm.nih.gov/clinvar/variation/

CAID: N/A

gnomAD: 0.000003976 https://gnomad.broadinstitute.org/variant/3-10188319-A-G

VariantEvidence: N/A

MutationType: synonymous_variant

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

MultipleGeneVariants: N/A

GroupID/ KindredID: F35

Case: Sex unknown, 21Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found with pancreatic tumors

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

CaseHPOFreeText: Age of onset is 21Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F15

Case: Sex unknown, 32Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Noted of familial antecedents of phaeochromocytoma.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Unilateral pheo. Age of onset is 32Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175C (c.524A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36905 https://www.ncbi.nlm.nih.gov/clinvar/variation/36905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y175C (c.524A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F2

Case: Sex unknown, 26Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: None. Microsatellite analysis excluded nonpaternity for this patient, leading to the assumption that this variant was de novo in character. (assumed de novo without confirmation of maternity).

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

CaseHPOFreeText: cerebellar hemangioblastoma had multiple lesions. Age of onset is 26Y0M.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0009711 (clear cell renal cell carcinoma, pheochromocytoma, renal cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: F66

Case: Sex unknown, 12Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found of pancreatic cysts

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions on their retinal hemangioblastoma. Age of onset is 12Y0M.

CaseNotHPOs: HP:0006880; HP:0002666; HP:0000107; HP:0001737; HP:0006770 (cerebellar hemangioblastoma, pheochromocytoma, renal cysts, pancreatic cysts, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: F43

Case: Sex unknown, 27Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: Development of Broad ligament cysts were also observed. Age of onset is 27Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 5143

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Two members of this family were diagnosed with VHL Type 2B. Both members presented with pheochromocytoma, renal cell carcinoma and CNS hemangioblastoma and one of these also presented with retinal angioma.

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

CaseHPOFreeText: Diagnosed with CNS hemangioblastoma, pheochromocytoma, RCC and VHL Type 2B.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.713G>A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Variant reported as 713, G to A (Arg to Gln), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.500G>A, p.Arg167Gln (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 6104

DiseaseAssertion: VHL

GroupSize: 5

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:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: 2/5 members with pheochromocytoma, 3/5 members with CNS hemangioblastoma, 1/5 members with retinal angioma, 1/5 members with cysts, 1/5 with renal carcinoma. Diagnosed as a VHL Type 2B family.

GroupNotHPOs: N/A

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

GroupID: 37

DiseaseAssertion: hemangioblastoma

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 out of the 81 patients listed in this hemangioblastoma cohort were found with this c.499C>T mutation. Any relation is unknown.

GroupPresentingHPOs: HP:0010797 (hemangioblastoma)

GroupHPOFreeText: all patients had hemangioblastoma of the CNS; One patient was said to be found with a primary asymptomatic tumor. Other phenotypes are unknown.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 31

GroupID/ KindredID: 31

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161G (c.481C>G)

LegacyVariant: p.R161G (c.694C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 618484 https://www.ncbi.nlm.nih.gov/clinvar/variation/618484/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R161G (c.481C>G)

MultipleGeneVariants: N/A

PatientID: 40

GroupID/ KindredID: 40

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 1

GroupID/ KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

GroupID: II (from Hemangioma VHL Associated Group)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Studied 36 VHL-related pheochromocytoma by comparative genomic hybridization. In addition, we compared their genetic profiles with those of (1) multiple endocrine neoplasia type 2 (MEN 2)-related pheochromocytomas; (2) previously reported sporadic pheochromocytomas; and (3) VHL-related CNS hemangioblastomas.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had two VHL associated hemangioblastomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1 and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: VHL_5 (tumor ID)

KindredID: 5

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 30Y.

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

PatientID: 1

KindredID: 1

Case: F, 39Y0M, 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:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: The patient had a neuroendocrine tumour in the pancreas at age 37. A Pylorus-preserving pancreaticoduodenectomy was performed and the largest tumour resected was 24 mm. The patient was followed up 27.7 months later.

CaseNotHPOs: N/A

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

PatientID: 66

KindredID: 66

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: patient was not recorded to have an epididymal tumor, a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm), CCRCC, a neuroendocrine neoplasm (pheochromocytoma/paraganglioma), nor a CNS hemangioblamstoma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 29

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421 (Neuroendocrine neoplasm, pancreatic 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

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

PatientID: 46

KindredID: 46 **

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: ** Patients 46, 50, 71, and 72 were reported previously in Aronoff et al, 2018 (PMID: 29437867) as family 5

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: CNS hemangioblamstoma

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

CaseNotHPOFreeText: patient was not recorded to have an epididymal tumor, a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm), CCRCC, nor a neuroendocrine neoplasm (pheochromocytoma/paraganglioma)

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

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

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 32

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006770; HP:0010797; HP:0100634 (clear cell renal cell carcinoma, hemangioblastoma, neuroendocrine neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030405; HP:0009711; HP:0030421 (pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 1 - see here for more info)

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

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 61

KindredID: 61

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma; Epididymal neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0006770 (Neuroendocrine neoplasm, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 28

KindredID: 28

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0100634 (hemangioblastoma, clear cell renal cell carcinoma, neuroendocrine neoplasm)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma, CCRC, and a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm)

CaseNotHPOs: HP:0030421; HP:0030405; HP:0009711 (epididymal tumour, pancreatic endocrine tumour, retinal capillary hemangioma)

CaseNotHPOFreeText: patient was not recorded to have retinal hemangioblastoma, an epididymal tumor, nor a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

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

PatientID: II (son)

KindredID: F12

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 4 members of this family (I.mother, II.daughter, II.son, III.granddaughter) presented with pheochromocytoma and were found to have the P138= (c.414A>G) germline variant of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; synonymous_variant

CivicName: P138= (c.414A>G)

PatientID: II.1

KindredID: F1

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: N/A

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and kidney ischemic infarct at age 15 (DOB: 1991).

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: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition; splice_site_variant

CivicName: D143= (c.429C>T) and c.340+770T>C

MultipleGeneVariants: Germline, VHL, c.429C>T (p.Asp143Asp)

PatientID: V48

KindredID: V48

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.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

PatientID: V240

KindredID: V240

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL Type 2A.

CaseNotHPOs: N/A

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;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

GroupID: V32

DiseaseAssertion: VHL

GroupSize:2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Two family members had the same VHL gene mutation.

FamilyInfo: Positive.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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

PatientID: V59

KindredID: V59

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her fourth oldest sister had bilateral retinal angiomas, metastatic islet cell cancer, liver lesions, pancreatic endocrine tumours, and cerebellar hemangioblastoma. Her second oldest sister had two hypervascular pancreatic head tumours, a complex left renal cyst, and enlarged bilateral ovarian cysts. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. The oldest sister did not carry the mutation or have any abnormal presentations. The patient's mother was found to harbor the mutation and had retinal angiomas, bilateral adrenal pheochromocytoma, and pancreatic cysts. The patient's maternal grandmother was suspected to have VHL as she developed progressive blindness at age 32 and was completely blind by age 36. She died at age 68 due to an acute hemorrhage into and around a vascular tumour. The patient's maternal aunt died suddenly at age 51 due to a cerebellar hemangioblastoma. One of the aunt's children died at age 25 due to a cerebellar hemangioblastoma and another had bilateral retinal angiomas and multiple pancreatic cysts. Refer to Figure 1 for pedigree.

CasePresentingHPOs: HP:0009711, HP:0030405, HP:0002896 (retinal capillary hemangioma, pancreatic endocrine tumour, neoplasm of the liver)

CaseHPOFreeText: Presented with bilateral retinal angiomas. Abdominal CT revealed a pancreatic head mass and in surgery multiple 1 to 2 mm bilobar liver lesions were revealed. These were histologically confirmed to be metastatic islet cell disease.The primary pancreatic tumor that involved the superior mesenteric artery also demonstrated an islet cell neoplasm.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient's fourth oldest sister had bilateral retinal angiomas, metastatic islet cell cancer, liver lesions, pancreatic endocrine tumours, and cerebellar hemangioblastoma. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. Her youngest sister had bilateral angiomas, liver lesions, and metastatic islet cell cancer. The oldest sister did not carry the mutation or have any abnormal presentations. The patient's mother was found to harbor the mutation and had retinal angiomas, bilateral adrenal pheochromocytoma, and pancreatic cysts. The patient's maternal grandmother was suspected to have VHL as she developed progressive blindness at age 32 and was completely blind by age 36. She died at age 68 due to an acute hemorrhage into and around a vascular tumour. The patient's maternal aunt died suddenly at age 51 due to a cerebellar hemangioblastoma. One of the aunt's children died at age 25 due to a cerebellar hemangioblastoma and another had bilateral retinal angiomas and multiple pancreatic cysts. Refer to Figure 1 for pedigree.

CasePresentingHPOs: HP:0030405, HP:0000107, HP:0000138 (pancreatic endocrine tumour, Renal cyst, Ovarian cyst)

CaseHPOFreeText: The patient initially only presented with bilateral small ovarian cysts. On follow up four years later, it was found that she had two hypervascular pancreatic head tumours <1cm in diameter, a complex left renal cyst, and enlarged ovarian cysts. A pancreaticoduodenectomy and left heminephrectomy was performed, revealing two <1-cm islet cell tumours and a complex renal cyst with severe cellular atypia but no invasive maligancy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 7

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

CaseHPOFreeText: VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: c.340+1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 17

Case: Sex Unknown, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

CaseHPOFreeText: VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: c.463+2T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: 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

PatientID: 11

KindredID: 1112

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (Pancreatic endocrine tumor)

CaseHPOFreeText: The patient presented with one pathologic pancreatic neuroendocrine tumour at age 32. The tumour had metastasized.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant:p.E160Sfs*10(c.688delA)

CaseProblemVariantFreeText: N/A

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

PatientID: 10

KindredID: 2735

Case: F, 20Y0M, 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.Q73* (c.217C>T)

LegacyVariant: p.Q73* (c.430C>T)

CaseProblemVariantFreeText: N/A

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

CAID: CA357036 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.217C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 8

KindredID: IV

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None - considered VHL Type 1 due to the absence of pheochromocytoma and presence of pancreatic tumors.

CasePresentingHPOs: HP:0010797; HP:0002894 (hemangioblastoma; neoplasm of the pancreas)

CaseHPOFreeText: Patient had a CNS hemangioblastoma and a pancreatic tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V130F (c.601G>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Refer to table 3 for LOH information on VHL and ZAC1, and elongin-binding.

MutationType: missense_variant; transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A

GroupID: 33

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have the following mutation belonging to 2 families altogether. 

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

GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at age 18Y, 3 had cerebellar hemangioblastomas diagnosed at mean age of 18Y, and 1 had RCC diagnosed at 50Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R176Gfs*26 (c.526delA) 

LegacyVariant: N/A

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: R176fs (c.526del) 

MultipleGeneVariants: N/A

GroupID: 70

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.395A>C) was found in 1 VHL family with 2 patients.

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

GroupHPOFreeText: 1/2 patient had cerebellar hemangioblastoma (CHB) at 18Y, 1/2 had retinal capillary hemangioma (RH) at 37Y, and 1/2 had RCC at 49Y. Unclear as to which of the two patients these HPOs are paired to.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

GroupID: 8

Case: 37Y0M, 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:0005584; HP:0009711; HP:0006880 (renal cell carcinoma; retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had retinal angiomas diagnosed at 28Y, cerebellar hemangioblastomas diagnosed at 22Y, and renal cell carcinoma diagnosed at 37Y.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

GroupID: 81

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.506T>C) was found in 1 VHL family with 4 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas with a mean age of diagnosis of 22Y, and 2 patients had RCCs with a mean age of diagnosis of 28Y.

GroupNotHPOs: HP:0002666; HP:0006880 (pheochromocytoma, cerebellar hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.L169P (c.506T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428809 https://www.ncbi.nlm.nih.gov/clinvar/variation/428809/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L169P (c.506T>C)

MultipleGeneVariants: N/A

GroupID: 59

Case: 35Y0M, 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.256C>T) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 35Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

GroupID: 51

Case: 38Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.193T>C) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had retinal hemangioblastoma at age 38, and cerebellar hemangioblastoma at age 38.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

GroupID: 27

Case: 45Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 25Y, and RCC diagnosed at 45Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Q145* (c.433C>T) 

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q145* (c.433C>T) 

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: M, 15Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with bilateral pheochromocytoma at 11Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with unilateral pheochromocytoma at 15Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: M, 11Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with unilateral pheochromocytoma at 15Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: F, 41Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Of the patient’s three sons, two carried the mutation; one son presented with unilateral pheochromocytoma at 15Y, and another son presented with bilateral pheochromocytoma at 11Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 41Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: M, 9Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A - Details about the family history of this boy are unknown because the father left the family and his relations are unable to be found. Ten siblings from different fathers are healthy.

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

CaseHPOFreeText: metachronous paraganglioma adjacent to the opposite adrenal gland. A retropleural tumor was confirmed by MRI (of the fourth thoracic vertebra). MRI of the abdomen revealed a binodular tumor of 5 ! 2 ! 3 cm cranially and medially to the right kidney

CaseNotHPOs: N/A

CaseNotHPOFreeText: Internal and skin examination were unremarkable, especially café-au-lait spots of the skin were not present.

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65A (c.193T>G)

LegacyVariant: (c.406T>G)

CaseProblemVariantFreeText: A point mutation (406 T>G) found on exon 1, leads to the assumption of reference sequence used and Latif et al. (1993), translating to NM_000551.3 (c.406T>G).

ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 1

Case: M, 36Y0M, Turkish

DiseaseAssertion: VHL

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 mother, brother, two daughters, and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405 (adrenal pheochromocytoma; renal cell carcinoma; pancreatic endocrine tumor)

CaseHPOFreeText: Right adrenal (nonfunctional) pheochromocytoma, had a history of bilateral adenomectomy due to bilateral pheochromocytoma diagnosed when he was 12. He also has bilateral RCC and pancreatic neuroendocrine tumors

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

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

PatientID: IV-2

KindredID: 1

Case: F, 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 father, sister, grandmother and more, had the mutation. 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

PatientID: III-20

KindredID: 1

Case: M, 32Y0M, Turkish

DiseaseAssertion: VHL

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 likely inherited this from his father, and passed it onto his son. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: bilateral adrenal pheochromocytoma. He also had capsular invasion of his adrenal masses.

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

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

PatientID: III-4

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This female (III-4) appears to have inherited this disease from her mother and has passed it onto to her daughter thereafter. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

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

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This woman (II-1) appears to have inherited this disease from her father, and passed it onto her 6 children, and many kin thereafter. See Fig. 1 for family pedigree.

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

CaseHPOFreeText: Described as “probable” cerebellar hemangioblastoma and “probable” retinal angioma. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 1

Case: M, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (III-1) appears to have inherited this disease from his mother and passed it onto his kin thereafter. See Fig. 1 for family pedigree.

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

CaseHPOFreeText: Patient had cerebellar hemangioblastoma, along with retinal hemangiomas described as “probable”. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 19

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma; renal cell carcinoma)

GroupHPOFreeText: all (3) members had CNS hemangioblastomas, and 1 had RCC

GroupNotHPOs: HP:0009711; HP:0002666; HP:0001732 (retinal capillary hemangioma; pheochromocytoma; pancreatic lesion)

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: III-9

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: assumed VHL

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: VI-6

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

PatientID: V-37

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

PatientID: V-24

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

GroupID: 23

DiseaseAssertion: VHL

GroupSize:3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family presented with the c.499C>T germline variant of the VHL gene. Member 1037 had no renal involvement. Members 1035 and 1036 had 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:0005584 (Renal cell carcinoma)

GroupHPOFreeText: 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 15 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 1 or 50.

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

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

GroupID: 509

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to have the c.500G>A germline variant of the VHL gene. Member 11209 presented with mild renal disease (RCC), member 10939 had unknown renal involvement and members 10901 and 10902 had no 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: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]).

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.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

PatientID: None (Daughter)

KindredID: 12

Case: F, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: Mother has the same mutation and presented with renal cell caricnoma.

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 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 3708NCI

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 3708NCI. 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

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: p.L184P (c.764T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 12BMS

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: Family 12BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65* (c.194C>A)

LegacyVariant: p.S65* (c.407C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223161 https://www.ncbi.nlm.nih.gov/clinvar/variation/223161/

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: S65* (c.194C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 113CA

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 Family 113CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as a VHL family without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E186del (c.558_560del)

LegacyVariant: delGlu (c.771_773delGlu)

CaseProblemVariantFreeText: N/A

ClinVarID: 625264 https://www.ncbi.nlm.nih.gov/clinvar/variation/625264/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: E186del (c.558_560delAGA)

MultipleGeneVariants: N/A

GroupID/ KindredID: 52CA

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 52CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL familywith 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.S65L (c.194C>T)

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4942NCI, 4422NCI, 2005F

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 multiple databases, including: the Neuro Olcologie database in Paris, and the National Cancer Institute database, with an unknown number of members belonging to three family IDs: Family ID 4942NCI, 4422NCI, and 2005F. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as 3 VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

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

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 39CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 39CE. 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.S80N (c.239G>A)

LegacyVariant: p.S80N (c.452G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 8YO

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 8YO. 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.W88S (c.263G>C)

LegacyVariant: p.W88S (c.476G>C)

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

GroupID/ KindredID: 15

DiseaseAssertion: pheochromocytoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 patients are listed with this mutation; any relation is unknown. This mutation was said to be spontaneous.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: 2 members are stated to have pheochromocytoma. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161Q (c.695G>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

GroupID/ KindredID: VHL 7

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Croatian

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation belonging to VHL family 7

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

GroupHPOFreeText: all 3 patients has retinal capillary hemangiomas, but only 1 tally of hemangioblastomas of the central nervous system, renal cysts, and pancreatic cysts were listed.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+2T>C

CaseProblemVariantFreeText: The mutation was referred to in the paper as c.676+2C>T - which was corrected to c.676+2T>C with a footnote indicating the correction in relation to Glavac et al Hum Mutat 1996.

LegacyVariant: c.676+2C>T (or correction of c.676+2T>C)

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

PatientID: 220

KindredID: 82

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 81

KindredID: 27

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 81) had 3 family members confirmed with the mutation: his aunt 2 (patient 85) had pancreatic cysts and/or tumors at age 50, his cousin/ the son of Aunt 2 was asymptomatic at the time of assessment, and the granddaughter of aunt 2 was also asymptomatic at the time of assessment. The proband also had 3 family members who passed away before diagnosis/ before confirming the mutation: his mother (patient 82) had a CNS hemangioblastoma at 33, his Aunt 1 (patient 83) had a CNS hemangioblastoma at 32, and his cousin/ the son of Aunt 1 (patient 84) had a CNS hemangioblastoma at 30.

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0002666 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at age 28, and renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 38.

CaseNotHPOs: HP:0009711(Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: 160

KindredID: 61

Case: M, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a renal cell carcinoma at age 44.

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

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

PatientID: 8

KindredID: 5

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 21 and a multiple pancreatic cysts/tumors at age 30.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, 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.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

PatientID: 213

KindredID: 80

Case: M, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's son and sister were both confirmed to have this VHL mutation. Their son had a retinal angioma at 26 and a pheochromocytoma at 31. Their sister had a pheochromocytoma at 14. Their mother had renal cell carcinoma at 56, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 52.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 233

KindredID: 86

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 229) had a sister (patient 230) who was genetically confirmed with the mutation, and presented with a CNS hemangioblastoma at age 40. The proband's brother 1 (patient 231) was also confirmed with the mutation and had a retinal angioma at 25, and renal cell carcinoma at 54. The proband's brother 2 passed away before they could be diagnosed/ confirmed with the mutation, but they had a CNS hemangioblastoma at 35. Finally, the proband's nephew (son of brother 2) was genetically confirmed with the mutation and presented with renal cell carcinoma at age 30.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband's nephew (son of brother 2) (patient 233) had a renal cell carcinoma at age 30.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732; HP:0009711; HP:0010797 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Retinal capillary hemangioma, 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.L178R (c.533T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625261, https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A 33Y male patient (patient #40, family #13) was confirmed for a missense mutation in the VHL gene (c.239G>T; p.Ser80Ile). He was diagnosed with renal cell carcinoma at 31Y, multiple pancreatic cysts or tumours at 31Y, pheochromocytoma at 31Y, and retinal angioma at 33Y. No family history is reported. This patient was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 71

KindredID: 25

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband has the same mutation as her son (patient no.72). Her son did not present with hemangioblastoma, multiple pancreatic cysts/tumors, retinal angioma, renal cell carcinoma, or pheochromocytoma, and is apparently asymptomatic.

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

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 28, multiple pancreatic cysts/tumors at age 28, and hemangioblastoma at age 30.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A