PatientID: III:2

KindredID: 1

Case: F, 62, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her daughter (IV:2) had three children and one was found to carry the mutation. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:3 and III:11). Patient III:3 had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: RCC-23

KindredID: 1

Case: Sex and Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0006770 (Clear cell renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

200 patients with intracranial aneurysms were molecularly analyzed for VHL to determine if it is a candidate gene for aneurysm formation using peripheral blood. One patient was analyzed in detail and determined to have the above mutation (74C>T). The patient was only recorded to have an intracranial aneurysm (or dilatation of the cerebral artery).

Thirteen patients from four families (A, B, C and D) with known VHL disease and known mutations in the VHL gene were examined.  MLPA using venous blood showed 4 genetic variants. Family C was found with a p.L198P mutation in the VHL gene, only confirmed in patient II-1 (male), and was identified together with the polymorphism c.74C>T, p.P25L. The asymptomatic father was also a carrier of the same polymorphism (c.74C>T, p.P25L). No further familial information was provided although suggestion of a de novo mutation. Patient II-1 presented with adrenal pheochromocytoma. pancreatic neuroendocrine tumour, and retinal hemangioblastoma.

PCR amplification was performed searching for point mutation in the entire VHL coding sequence and promoter region, including exon-intron boundaries. Amplification was performed in a Gene Amp PCR System 9700 (Perkin Elmer). When mutations were detected in DNA from tumor samples, it was searched for in the corresponding peripheral blood DNA in order to identify germline mutations. For case 3, table 2 described no mutations found through analysis of HB and peripheral blood. Case 3 was thus said to have sporadic, non-familial disease - however, her sister at 53Y had a single cerebellar hemangioblastoma, with 1 germline and 2 somatic point mutations. These are described further in PMID: 24335534 as P25L(c.74C>T) [germline], D126Rfs*6(c.375_376insA) [somatic], and E55Rfs(c.163delG) [somatic]. It is unclear as to whether the germline mutation was confirmed in case 3.