PatientID: 8

KindredID: 8

Case: F, 49Y0M, Korean

DiseaseAssertion: Assumed VHL

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0006880 (adrenal pheochromocytoma, renal cell carcinoma, cerebellar hemangioblastoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma. She also had other tumours, including renal cell carcinoma and cerebellar hemangioblastoma (see table 3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, NF1, MAX, SDHA/SDHAF2/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053, https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1 (group ID 5)

Case: M, 68Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 1 had a daughter, and 3 grandkids with this mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: He had an age of onset for RCC at 65Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 1 (group ID 5)

Case: F, 32Y0M, Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 15’s mother and grandfather had this familial mutation, as well as her sister and brother. Her son tested negative. See Fig 4 for family pedigree; Table 3 for details.

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

CaseHPOFreeText: She had RCC and pancreatic cysts at 30Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 VHL family members (VHL family 3). One had hemangioblastomas of the central nervous system and one had retinal angiomas. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Of these, 21 patients from two families were found to harbour the VHL germline mutation c.262T>C (p.Trp88Arg). From family 1, a total of 17 family members including the proband were identified. Three of these did not present VHL clinical features. The 32 year old proband (patient 15) presented with pancreatic neuroendocrine tumor or pancreatic cyst and renal cell carcinoma. Her maternal grandfather presented with renal cell carcinoma at age 65. Her maternal great-uncle (patient 3), great-aunt (patient 4), mother (patient 6) and 6 first cousins once removed (patients 7, 8, 9, 10, 13, 14) each presented with cerebellar hemangioblastomas at ages 62, 37, 35, 41, 40, 35, 29 37 and 37 respectively. One of these cousins (9) also presented with renal cell carcinoma at age 42. Two other 1st cousins once removed (patients 11 and 12) presented with renal cell carcinoma at ages 35 and 40, as did her sister at the age of 27. From family 2, the proband presented with no clinical features, however, her mother (2) presented with pancreatic cancer at age 45. Both her maternal uncle (patient 3) and grandmother (patient 1) presented with cerebellar hemangioblastomas at ages 50 and 48 respectively. This same uncle also had pheochromocytoma, also identified at the age of 50. ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members (both families 1 and 2), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 4

KindredID: 2 (group ID 5)

Case: F, 31Y0M, Chinese

DiseaseAssertion: asymptomatic

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 2, 4 members were described in a 3 generation family. The proband’s mother, uncle, and grandfather were also present with the VHL mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: N/A

CaseHPOFreeText: No characteristics were described

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 1 (group ID 5)

Case: M, 40Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 12’s mother and brother had this familial mutation. His two daughters had not been yet tested at the time of the study. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: He had RCC at 40Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 2 (group ID 5)

Case: M, 52Y0M, Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 2, 4 members were described in a 3 generation family. The patient’s father, sister, and niece were also present with the VHL mutation. See Fig 4 for family pedigree; Table 3 for details.

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

CaseHPOFreeText: CNS hemangioblastoma and pheochromocytoma both presented at age of onset of 50Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 1 (group ID 5)

Case: M, 48Y0M, Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 8’s father and sister had this familial mutation. His one son had not been yet tested at the time of the study. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: He had CNS hemangioblastomas at 40Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A