PatientID: 84

KindredID: 84

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.R107H (c.320G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223184, https://www.ncbi.nlm.nih.gov/clinvar/variation/223184/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R107H (c.320G>A)

MultipleGeneVariants: N/A

PatientID: 86

KindredID: 86

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.L163I (c.487C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L163I (c.487C>A)

MultipleGeneVariants: N/A

PatientID: 94

KindredID: 94

Case: Sex Unknown, 27Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 26.95 was detected. Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.Y156H (c.466T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756040

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y156H (c.466T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006748, HP:0100827, HP:0001894, HP:0009713, HP:0031496 (Adrenal pheochromocytoma, lymphocytosis, thrombocytosis, spinal hemangioblastoma, mucinous cystic neoplasm of the pancreas)

CaseHPOFreeText: At age 45 the patient was admitted for 2-week history of fatigue and muscle weekness. MRI showed bilateral chronic infarcts resulting from multiple cryptogenic strokes in his past medical history. Blood tests revealed unexplained lymphocytosis and thrombocytosis.The patient was found to have bilateral adrenal phoechromocytomas, hemangioblastomas in the spinal cord at T11 and in the cauda equina at L2, and multiple intraductal papillary mucinous neoplasms.

CaseNotHPOs: HP:0005584, HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 16Y0M, Ukrainian

DiseaseAssertion: Assumed VHL

FamilyInfo: Her brother (patient 2) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901, HP:0005954, HP:0000077, HP:0001028 (polycythemia, pulmonary capillary hemangiomatosis, abnormality of the kidney, hemangioma )

CaseHPOFreeText: Patient had a hematocrit of 68%, erythropoietin level of 45 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo. She was diagnosed with polycythemia of unknown duration; at the age of 10 years, a pulmonary angioma was found and treated by a coil embolization. She continued to be polycythemic. At the age of 15 years, an abdominal computed tomography (CT) scan revealed a left renal mass, which on nephrectomy was determined to be a subcapsular hemangioma; there was no evidence of an angioma elsewhere. One year after surgery, she still remains polycythemic but has no evidence of a new or recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

MultipleGeneVariants: N/A

PatientID: None (Cousin 2)

KindredID: G

Case: Sex Unknown, 38Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 38, pheochromocytoma at age 39 and retinal hemangioblastoma at age 29. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: V-2

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

CasePresentingHPOs: HP:0010797; HP:0000107 (Hemangioblastoma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma and renal cyst. Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: V-1

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

CasePresentingHPOs: HP:0010797; HP:0000107 (Hemangioblastoma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma and renal cyst. Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: IV-4

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

CasePresentingHPOs: HP:0000107; HP:0010797 (Renal cyst, Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma and renal cyst. Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: W

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Parents unavailable for testing. No prior family history of VHL.

CasePresentingHPOs: HP:0010797, HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0002894, HP:0002666 (retinal capillary hemangioma, neoplasm of the pancreas, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: c.677-1G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.464-1G>A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0006770, HP:0030405, HP:0004510 (clear cell renal cell carcinoma, pancreatic endocrine tumour, Pancreatic islet-cell hyperplasia)

CaseHPOFreeText: At age 40 the patient presented with left sided clear cell renal cell carcinoma, islet cell hyperplasia, and pancreatic endocrine tumour. 46 months later the patient has no evidence of recurrence.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: Both the hyperplastic islet cells and pancreatic microadenomas stained negatively for marker upon immunohistochemical testing for hypoxia-inducible factor (HIF)-1α.

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 74

KindredID: 74

Case: Sex Unknown, 31Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Single benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: Complete Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 34.31 was detected. Membrane CA9 immunostaining was observed.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 47

KindredID: 47

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.Y156S (c.467A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756049

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y156S (c.467A>C)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 42

Case: Sex Unknown, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 40/41

KindredID: 40/41

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Patient data is extracted from two rows assumed to be referring to the same patient (i.e. tumor samples 40 and 41 in Supplementary Table 1a). Carbonic anhydrase 9 (CA9) mRNA level of 795.70 (PCC) and 815.38 (PCC) were detected. Membrane CA9 immunostaining was observed in both PCC samples.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: His brother and grandfather had the same VHL mutation. His mother also had this mutation and presented with pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, and spinal hemangioblastoma.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

ClinVar: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>A)

MultipleGeneVariants: N/A