PatientID: None

KindredID: 20

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0001737; HP:0005584; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cyst, pancreatic cysts, renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: At initial screening, patient was found with 2 HB, unilateral retinal capillary hemangioma, 1 renal cyst, 1 pancreatic cyst, and 1 pheochromocytoma. By final screening, the 5 year follow up, there was an additional RCC and pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162F (c.485G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43604 https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162F(c.485G>T)

MultipleGeneVariants: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 698G>A) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.485G>A (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb), renal cell carcinoma (RCC), and pheochromocytoma was available. Case 11 had a p.Cys162Tyr (c.485G>A) mutation. 4 members were affected with CNS Hb. Other demographics of the members were not described.

Seven VHL mutations were identified in 10 unrelated, Swedish families. Direct genome sequencing through Southern blot identified this missense mutation (c.485G>T) in family #5 with 2 affected members. One was found with renal cell carcinoma, retinal capillary hemangioma and CNS hemangioblastoma, whereas the other was found with renal cell carcinoma and retinal capillary. Other information on the affected member and relatives was not available.

Pathogenic variants from 10,389 individuals across 33 cancer types were examined from The Cancer Genome Atlas (TCGA) cohort. 12 of these individuals had a germline mutation in the VHL gene. The C162F (c.485G>T) missense VHL mutation was found in two African American females diagnosed with clear cell renal cell carcinoma, one of whom was 40Y0M and the other 55Y0M. No family information was provided on either patient.

GroupID: 69

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.C162F (c.485G>T)

LegacyVariant: c.698G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 43604, https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162F (c.485G>T)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The C162F (c.485G>T) germline missense mutation of the VHL gene was found in a 34 yr old VHL patient with multiple pancreatic cysts or tumors, pheochromocytoma, renal cysts, and central nervous system and retinal hemangioblastomas (index case 74).

GroupID/ KindredID: 5

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Swedish

GroupAgeRange: N/A

GroupInfo: 2 patients grouped under family 5 were found in this Swedish VHL family

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

GroupHPOFreeText: Both (2/2) had renal cell carcinoma, and retinal capillary hemangioma; only 1/2 had hemangioblastoma.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: neither patient had pheochromocytoma

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162F (c.485G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43604 https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162F (c.485G>T)

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A GroupEthnicity: Japanese GroupAgeRange: N/A

GroupInfo: The 4 patients are grouped based on both having the same mutation. They are unrelated to one another.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

GroupHPOFreeText: 4/4 patients in this group presented with CNS hemangioblastoma.

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

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

LegacyVariant: p.C233Y (c.698G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 43604, https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191492-G-T?dataset=gnomad_r2_1

VariantEvidence: Nucleotide deletion (i.e. 698G>A) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.485G>A (NM_000551.3).

MutationType: missense_variant;transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene was determined from peripheral blood. Family 3948 and family 4589 were found with c.485G>T mutations in the VHL gene (legacy notation c.698G>t converted to NM_000551.3). Family 3948: 1/4 had pheochromocytoma, 1/4 had renal cell carcinoma, 4/4 had CNS hemangioblastoma, 2/4 had retinal angiomas and 2/4 had cysts. Family 4589: 2/2 had pheochromocytoma and 1/2 had retinal angiomas. Individual patient phenotype-genotype was not described in the paper.