Our series comprised 125 eligible subjects with germlineVHL c.505 T/C mutation, including 64 previously known and 61 newly diagnosed mutation carriers.
GroupID: None
DiseaseAssertion: VHL
GroupSize: 125
GroupNumberMales: 58
GroupNumberFemales: 67
GroupEthnicity: German
GroupAgeRange: 4-86 Y
GroupInfo: The subjects included 64 patients belonging to 15 families with a known VHL c.505 T/C mutation. From their test programme, another 10 c.505 T/C mutation carriers were identified. As well, all consenting first degree relatives (at risk subjects) of mutation carriers, irrespective of disease status, were subjected to mutation analysis, resulting in another 51 mutation carriers detected.
GroupPresentingHPOs: HP:0002666, HP:0009713, HP:0009711, HP:0010797, HP:0006748, HP:0006737, HP:0006770, HP:0002893, HP:0100616, HP:0030357, HP:0002894 (pheochromocytoma, spinal hemangioblastoma, retinal capillary hemangioma, hemangioblastoma, adrenal pheochromocytoma, extraadrenal pheochromocytoma, clear cell renal cell carcinoma, pituitary adenoma, testicular teratoma, small cell lung carcinoma, neoplasm of the pancreas)
GroupHPOFreeText: 96 patients had clinical manifestations of VHL. 55 subjects (31 males, 24 females) developed pheochromocytoma during their lifetime. Overall penetrance for pheochromocytomas was estimated to be 31% by age 35 and 60% by age 70. Other frequent lesions were retinal angioma (36%), hemangioblastoma of the spine (36%), and, to a lesser extent, hemangioblastoma of the brain (16%). One patient with angiomatosis retinae developed at least 25 retinal angiomas, whereas the remaining patients had an average of two angiomas with no more than five lesions in one patient. 15 patients had bilateral and 25 unilateral involvement of the retinae. Pheochromocytoma was observed as a single tumour with adrenal or extra-adrenal localization in 32 patients, but 23 mutation carriers developed multiple pheochromocytomas. Four patients developed renal clear cell carcinoma (estimated overall penetrance 13% by the age of 70). Two of these patients died of metastases. All renal clear cell carcinomas were unilateral, single tumours, and no kidney showed renal cysts. Three of the patients with renal cell carcinoma were female. The kidney tumours were detected at the ages of 46 (male patient), 48, 63, and 74 years. Two patients with renal cell carcinoma also had multiple spinal hemangioblastomas. Other rare tumours were one pancreatic islet cell tumour and one pituitary adenoma; both neoplasms had been incidentally found in a dead 34 year old woman at necropsy. One 68 year old male patient was noted to have small cell lung cancer, and two other males developed testicular teratocarcinoma both at 39 years of age.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: p.Y98H (c.505T>C)
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