PatientID: I-a

KindredID: 1

Case: M, 50Y0M, Greek

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s 16Y daughter presented with spinal hemangioblastoma at 12Y, retinal hemangioblastoma and pancreatic cysts at 13Y, and cerebellar hemangioblastoma at 16Y. She was also found to carry the mutation NM_000551.3:c.433C>T that the patient carried. The patient’s other two children, an 18-year-old son and a 20-year-old daughter are phenotypically healthy and repeated biochemical evaluation and imaging studies are negative. The patient’s siblings and nephews are also phenotypically healthy with no indications from either biochemical or imaging studies as they denied further evaluation. In addition, the patient’s father of unknown genotype died at the age of 85 years while his mother is alive and has no problems, being 86 years old at time of writing.

CasePresentingHPOs: HP:0009713; HP:0009711 (Spinal hemangioblastoma, retinal hemangioblastoma)

CaseHPOFreeText: The 50Y male patient has retinal HBs diagnosed at the age of 20 years, treated by repeated courses of laser photopexy and cryotherapy. He also has spinal cord HBs located in the neck and cauda equina, treated surgically.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145*(c.433C>T)

LegacyVariant: N/A

ClinVarID: 625249, https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

gnomAD: N/A

VariantEvidence: It has been documented that dynamic organisation of pVHL–HIF1α recognition is focally centred on Gln145 within the L7 loop, and its tumourigenic mutant Q145H abolishes almost all of the correlated dynamic motions. In this report, Q145 is substituted by a stop codon, p.Q145X. This is a nonsense mutation resulting to a truncated VHL protein that lacks the last 68 amino acids and thus its function is abolished.

MutationType: stop_gained

CivicName: Q145*(c.433C>T)

MultipleGeneVariants: N/A

PatientID: IV-6

KindredID: 2

Case: F, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her 48Y father (Patient III-4) presented with hematuria at age 39Y and was found to have clear-cell renal-cell carcinoma, renal cysts, pancreatic cysts, and multiple hemangioblastomas of the cerebellum and lower brainstem. Her father was found to have mosaic VHL disease and the NM_000551.3:c.227_229del mutation the patient carried in approximately one of seven peripheral blood lymphocytes. The patient’s mother was unaffected. Of the patient’s three sisters and two brothers, one underwent clinical examination and two underwent genetic testing of unclear nature, and were found to be unaffected. The remaining two siblings were not evaluated.

CasePresentingHPOs: HP:0009713; HP:0001737; HP:0000107; HP:0000077; HP:0009711 (Spinal hemangioblastoma, pancreatic cyst, renal cyst, renal lesion, retinal hemangioma)

CaseHPOFreeText: The 23Y female patient was diagnosed with VHL disease at age 15 years, when she developed symptoms caused by spinal cord hemangioblastomas. At age 20 years, she was diagnosed with multiple cystic lesions in the right kidney, a solid lesion of the left kidney, multiple pancreatic cysts, and a small peripheral retinal angioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del(c.226_228delTTC)

LegacyVariant: p.F76del(c.439_441delTTC)

ClinVarID: N/A

CAID: CA357012

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del(c.226_228delTTC)

MultipleGeneVariants: N/A