PatientID: None (Daughter)

KindredID: 25

Case: M, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: Familial VHL. Two sons and a daughter presented with the same VHL germline mutation. All of these children presented with CNS hemangioblastomas. One of these sons also had renal cell carcinoma and was noted to have further unspecified phenotypes. His sister also had co-occurring unspecified phenotypes.

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: Multiple or bilateral CNS hemangioblastomas. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.01119, https://gnomad.broadinstitute.org/variant/3-10183876-G-C?dataset=gnomad_r2_1

VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism).

MutationType: missense_variant;transversion; splice_site_variant

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 139CA

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 139CA. 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: c.340+5G>C

LegacyVariant: (c.553+5G>C)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism). This paper declares this cariant is predicted to compromise the Elongin-binding site either by truncating the protein or by location between codons 157 and 189.

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: sister

KindredID: C

Case: F, 34Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Family history is positive. Patient’s sister, and son all had the splice mutation, two with CNS hemangioblastomas and one with pheochromocytoma

CasePresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, papillary cystadenoma of the epididymis)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y, and adnexal papillary cystadenoma of probable mesonephric origin diagnosed at 35Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: proband

KindredID: C

Case: F, 29Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is positive. Patient’s sister, and nephew all had the splice mutation, and sister and nephew had CNS hemangioblastomas and adnexal papillary cystadenoma of probable mesonephric origin, and pheochromocytoma phenotypes. Her daughter was asymptomatic and did appear to not carry the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 29Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 7

KindredID: III

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had three other family members with additional CNS hemangioblastomas and the same splice site mutation. Their one family member, patient 4, also presented with pancreatic tumors.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient was recorded with 3 labelled CNS hemangioblastoma tumors (a, b, and c).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious). Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 6

KindredID: III

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had three other family members with additional CNS hemangioblastomas and the same splice site mutation. Their one family member, patient 4, also presented with pancreatic tumors.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious). Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: None (Son 2)

KindredID: 25

Case: M, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: Familial VHL. Two sons and a daughter presented with the same VHL germline mutation. All of these children presented with CNS hemangioblastomas. One of these sons also had renal cell carcinoma and was noted to have further unspecified phenotypes. His sister also had co-occurring unspecified phenotypes.

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817 and/or 19949673

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.01119, https://gnomad.broadinstitute.org/variant/3-10183876-G-C?dataset=gnomad_r2_1

VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism).

MutationType: missense_variant;transversion; splice_site_variant

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

MultipleGeneVariants: N/A

GroupID: 42

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

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

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A