In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 5 VHL type 2 family members (family ID 2547), using PCR and SSCP sequencing. The mutation of c.278G>A was referred to in the paper by c.491G>A due to a difference in transcript sequence. Three of 5 individuals were identified with retinal hemangioblastomas, 4 with CNS hemangioblastomas, and 2 with pheochromocytoma.

GroupID: 2

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: Neuroendocrine neoplasm (pheochromocytoma or paraganglioma)

FamilyInfo: This mutation (p.G93D (c.278G>A)) was found in a patient with a family history and/or a syndromic presentation.

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: Patients with a pheochromocytoma or a functional paraganglioma were recruited from several different French clinical centers participating in several clinical research networks (Cortico et Medullosurrènale: les Tumeurs Endocrines, Paragan-Glioma Network, Groupe des Tumeurs Endocrines)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, NF1, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

GroupID: 2547

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

GroupHPOFreeText: 3/5 members had a retinal angioma (hemangioma), 4 had CNS hemangioblastoma, and 2 had pheochromocytoma

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 2547NCI);

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.G164D (c.491G>A )

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. One family with 4 patients (Family ID 3) were found with a germline missense mutation in the VHL gene (G93D; c.278G>A). Patient 1 was diagnosed at 7Y and had no manifestations by the end of the study at 18Y old. Patient 2 and 3 were both diagnosed at 9Y and and both developed pheochromocytoma at age 15Y. They were both 20Y at the end of the study. Patient 4 was diagnosed at 10Y and had 2 pheochromocytomas at age 12Y, and 1 retinal hemangioblastoma at age 10Y. They were 21Y at the end of the study.

PatientID: IV

KindredID: 3

Case: Sex Unknown, 21Y0M, Danish

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for PNETs either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. One patient (20), a 68-year-old male, was found to harbour the c.278G>A mutation in the VHL gene (stated as 491 G to A in the paper which used the Latif sequence as reference) leading to an amino acid change of Gly to Asp at protein position 93. He presented with a single radiologic pancreatic neuroendocrine tumor. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 21

KindredID: 21

Case: M, 32Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for VHL. No details provided.

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

CasePresentingHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastoma. Multiple or bilateral pheochromocytoma. Pheochromocytoma. Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A