Four patients from the same family carrying missense VHL mutation c.509 T>G were screened for VHL related lesions. Patient 1, 30Y F, had undergone treatment for pancreatic endocrine tumors and pheochromocytoma. Patient 2, 30Y M, was affected by retinal angioma, bilateral adrenal pheochromocytoma and sacral, intercarotid paraganglioma. Patient 3 underwent treatment for pheochromocytoma. Investigations revealed additional pancreatic endocrine tumor and a pheochromocytoma. Patient 4 had an endocrine pancreatic tumor and a pheochromocytoma. ACMG: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology.

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.509T>G), affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma diagnosed at 33Y, and 1 with pheochromocytoma diagnosed at 29Y. This mutation was reported in the paper with an incorrect cDNA written as c.509T>C, however correct translation should be c.509T>G given the Latif et al. (1993): c.722T>G (Val170Gly)

PatientID: 53

KindredID: 53

Case: Sex Unknown, 37Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0001732; HP:0010797; HP:0000107 (Clear cell renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A