PatientID: 2

KindredID: 2

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history. He was offered clinical surveillance due to a family history of known VHL and genetic testing that revealed him positive for the family-specific VHL mutation. The father and two brothers have been treated for multiple retinal, cerebellar, and spinal cord hemangioblastomas, although it did not clearly state whether they all carried the mutation.

CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

CasePresentingHPOs: HP:0040277; HP:0002668; HP:0001737; HP:0006770 (neoplasm of the pituitary gland, paraganglioma, pancreatic cyst, clear cell renal cell carcinoma)

CaseHPOFreeText: Originally asymptomatic at age 29Y, clinical surveillance revealed a pituitary tumor. At age 34, he had painful swelling on left neck where a mass was found, and CT disclosed a left carotid body tumor (paraganglioma)(later resected). At age 41, multiple pancreatic cysts were detected and a left kidney cancer that was resected (histologically showed clear cell carcinoma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135 (c.404T>A) OR p.L135 (c.404T>G)

CaseProblemVariantFreeText: As the publication only provides the p., the exact mutation is not known. p.L135* can translate to either c.404T>A or c.404T>G

LegacyVariant: N/A

ClinVarID:

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was unremarkable and proband has no children.

CasePresentingHPOs: HP:0006770; HP:0006880; HP:0001737; HP:0001289; HP:0005584 (Clear cell renal cell carcinoma, Cerebellar hemangioblastoma, Pancreatic cysts, Confusion, Renal cell carcinoma)

CaseHPOFreeText: Presented at age 39 with bilateral renal tumors (2 right side, 3 left side). Pathological evaluation revealed clear cell type renal cell carcinoma (fig. 1, B). After 2 years multiple pancreatic cysts were noted. Two years later 6 bilateral renal cell carcinoma lesions developed. Five years later at age 48 years mental confusion developed and brain MRI showed a cerebellar lesion; histological evaluation revealed cerebellar hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: ex. p.C162W (c.486C>G)

LegacyVariant: c.699C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Both of the patient’s brothers (Patient II-3 and II-4), the patient’s sister (II-5), and the patient’s nephew (III-3) were clinically diagnosed with VHL disease. Patient II-4 presented with RCCC at age 53, and carried the mutation NM_000551.3:c.269A>T. Patient III-3 presented with CH and carried the same mutation. The patient’s other brother (Patient II‐3) and sister (Patient II‐5) were deceased and had an undetermined mutation. Patient II-3 died of an advanced RCCC, and Patient II‐5 died of a ruptured CH. The patient’s parents (Patient I-1 and I-2) were also deceased from other causes. The patient’s grand-nephew (Patient IV‐1) was healthy and did not carry the mutation.

CasePresentingHPOs: HP:0006770; HP:0006880 (Renal clear cell carcinoma, cerebellar hemangioblastoma)

CaseHPOFreeText: The 45Y male patient was diagnosed with left RCCC at 33Y, but had no symptoms. The patient presented with complaints of headache and dizziness at age 41Y, and was diagnosed with a right cerebellar hemangioblastoma. In the most recent follow‐up, his symptoms had disappeared, and radiological imaging of the brain and abdomen revealed no recurrence.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient.

Variant: p.N90I (c.269A>T)

LegacyVariant: N/A

ClinVarID: 223172, https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I(c.269A>T)

MultipleGeneVariants: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient