PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient's fourth oldest sister had bilateral retinal angiomas, metastatic islet cell cancer, liver lesions, pancreatic endocrine tumours, and cerebellar hemangioblastoma. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. Her youngest sister had bilateral angiomas, liver lesions, and metastatic islet cell cancer. The oldest sister did not carry the mutation or have any abnormal presentations. The patient's mother was found to harbor the mutation and had retinal angiomas, bilateral adrenal pheochromocytoma, and pancreatic cysts. The patient's maternal grandmother was suspected to have VHL as she developed progressive blindness at age 32 and was completely blind by age 36. She died at age 68 due to an acute hemorrhage into and around a vascular tumour. The patient's maternal aunt died suddenly at age 51 due to a cerebellar hemangioblastoma. One of the aunt's children died at age 25 due to a cerebellar hemangioblastoma and another had bilateral retinal angiomas and multiple pancreatic cysts. Refer to Figure 1 for pedigree.

CasePresentingHPOs: HP:0030405, HP:0000107, HP:0000138 (pancreatic endocrine tumour, Renal cyst, Ovarian cyst)

CaseHPOFreeText: The patient initially only presented with bilateral small ovarian cysts. On follow up four years later, it was found that she had two hypervascular pancreatic head tumours <1cm in diameter, a complex left renal cyst, and enlarged ovarian cysts. A pancreaticoduodenectomy and left heminephrectomy was performed, revealing two <1-cm islet cell tumours and a complex renal cyst with severe cellular atypia but no invasive maligancy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.R167Q (c.500G>A)

LegacyVariant: c.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: III-4

KindredID: Family A

Case: F, 38Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. Her mom II-2 had confirmed VHL and CNS hemangioblastoma; and her cousin (III-6) has renal cell carcinoma and CNS/spinal hemangioblastoma and also the confirmed VHL gene mutation. Her uncle (II-3) has confirmed VHL gene and pancreatic and renal cysts. Her brother and sister (III-3; III-5) both were found with the confirmed VHL gene mutation; with retinal hemangioblastoma and CNS/spinal hemangioblastomas. IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

CasePresentingHPOs:HP:0001737; HP:0000138 (pancreatic cyst; ovarian cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711; HP:0010797 (renal cell carcinoma, pheochromocytoma, retinal capillary hemangioblastoma, CNS hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 deletion

MultipleGeneVariants: N/A

PatientID: VHL-14

KindredID: 14

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

CasePresentingHPOs: HP:0010797, HP:0001737, HP:0009711, HP:0000138 (hemangioblastoma, pancreatic cysts, retinal capillary hemangioma, ovarian cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584, HP:0002666 (Renal cell carcinoma, pheochromocytoma )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526679 https://www.ncbi.nlm.nih.gov/clinvar/variation/526679/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.463+1G>A

MultipleGeneVariants: N/A