PatientID: HGB-65

KindredID: 8

Case: Sex Unknown, 31Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

CasePresentingHPOs: HP:0006880, HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

CaseHPOFreeText: The patient had a multiple cerebellar hemangioblastomas at age 26. The cerebellar hemangioblastomas reoccured at age 29. The patient had a spinal hemangioblastoma at age 30.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E173* (c.517G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 825515 https://www.ncbi.nlm.nih.gov/clinvar/variation/825515/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E173* (c.517G>T)

MultipleGeneVariants: N/A

The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic. 8 patients had germline VHL mutations. Both peripheral blood and tumor tissue samples were sequenced using Big Dye Terminator Ready Reaction mix v.1.1 (Life Technologies, Foster City, CA). Sequencing reactions were loaded on an ABI 3100 capillary sequencer (Life Technologies) and analyzed using the Sequencing Analysis software v.3.7 (PE Applied Biosystems, Grand Island, NY). One Italian patient (HGB-65) with a germline nonsense mutation (c.517G>T; p.Glu173*) in the VHL gene was diagnosed at age 26 with multiple cerebellar hemangioblastomas, reoccurrence at 29Y, and spinal hemangioblastoma at 30Y. The patient has a negative family history for VHL disease.

43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 1 (patient VHL-4) of the 43 patients was found to have the Glu173Ter (c.517G>T) germline mutation of the VHL gene. Genotyping was performed on peripheral blood executed via direct sequencing on an automatic sequencer and real time quantitative PCR. Clinical manifestations associated with this mutation include: CNS hemangioblastoma, bilateral renal cell carcinoma, and retinal hemangioblastoma. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.