PatientID: 1

KindredID: 1

Case: F, 44Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient has a notable family history. Her eldest brother had multiple RCCs in both kidneys, bilateral cerebellar hemangioblastomas, and pheochromocytoma in his left adrenal gland (see Patient 2). Her daughter also underwent cortex-sparing adrenalectomies for bilateral pheochromocytomas as well as hemangioblastoma resection in her left cerebellum at age of 19 years, although no testing for VHL was stated.

CasePresentingHPOs: HP:0006748, HP:0030405, HP:0006880, HP:0000107, HP:0005584 (adrenal pheochromocytomas, pancreatic endocrine tumour, cerebellar hemangioblastoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: Patient diagnosed at age 29 with bilateral pheochromocytomas when she presented with severe hypertension and two large masses (greater than 6 cm) in her bilateral adrenal glands. At 38 years old, she underwent a resection for a mass found on her pancreas, with pathological analysis of the mass revealing a pancreatic neuroendocrine tumor. At 42 years old, a follow-up CT scan revealed two heterogeneous contrast-enhanced masses, one on the right kidney and one on the left adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

ClinVar: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAiD: CA16621914 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her youngest sister had bilateral angiomas, liver lesions, and metastatic islet cell cancer. Her second oldest sister had two hypervascular pancreatic head tumours, a complex left renal cyst, and enlarged bilateral ovarian cysts. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. 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:0009711, HP:0006880, HP:0030405, HP:0002896 (retinal capillary hemangioma, cerebellar hemangioblastoma, pancreatic endocrine tumour, neoplasm of the liver)

CaseHPOFreeText: Presented with bilateral retinal angiomas and cerebellar hemangioblastoma at age 29. Three months later presented with abdominal pain which was found to be due to metastatic islet cell cancer. Laparotomy revealed multiple 1 to 2 mm bilobar liver lesions but the primary pancreatic tumour was unresectable because of involvement of the superior mesenteric artery.

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