PatientID: 1

KindredID: A (II-5)

Case: M, 64Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (I:1) died of renal cell carcinoma at age 55. The patient had seven siblings. His brother (II:3) died of cerebellar hemangioblastoma at age 39 and another (II:11), also died of cerebellar hemangioblastoma at age 33. His sister (II:7) was found to carry the mutation and presented with renal cell carcinoma, hemangioblastoma, and pheochromocytoma. Another sister (II:13) who did not undergo genetic testing, presented with hemangioblastoma. Brother (II:1) died of unknown causes and another brother (II:9) was asymptomatic and did not undergo genetic testing. The patient had four children; one was asymptomatic (III:9), another (III:6), the third (III-7) had a retinal angioma had a hemangioblastoma, and a daughter (III-8) had pheochromocytoma. Patient III-8 is the only child from this family who underwent genetic testing and was found to carry the mutation. Some of his nieces and nephews presented with VHL related phenotypes and were found to harbour the mutation. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0009711, HP:0002666, HP:0000107 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pheochromocytoma, renal cyst)

CaseHPOFreeText: Diagnosed with renal cell carcinoma at age 42. Underwent radical nephrectomy of both the right and left side. He had five renal cell carcinomas and 15 renal cysts. The patient was on dialysis. He had a satellite lesion.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: A (III-8)

Case: F, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's father (II-5) harbored the mutation and presented with hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pheochromocytoma, and renal cysts.The patient had three siblings, none of whom underwent genetic testing. Of the three only one was healthy (III-9). One of her brothers (III-6) had hemangioblastoma and the other brother (III-7) had retinal angioma. On the father's side of the family there was extensive history of VHL disease. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: At 24, she was diagnosed with renal cell carcinoma. She underwent nephron-sparing surgery of the left side and one RCC measuring 5 cm in diameter was removed. There was a complication post-op; haemorrhage and urinary tract infection.

CaseNotHPOs: HP:0010797, HP:0009711 (hemangioblastoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: VCB.04T

KindredID: 5

Case: Sex Unknown, 24Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma, pheochromocytoma)

CaseHPOFreeText: Presented with bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127

PreviouslyPublished: 25545346 (see table S1 and S10)

SupplementalData: Yes

Variant: p.V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573119327 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573119327

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: Unknown

Case: F, 28Y0M, Dutch

DiseaseAssertion: VHL

FamilyInfo: Unknown - study sampled 15 patients from 5 families

CasePresentingHPOs: HP:0000107; HP:0009711 (renal cyst, retinal capillary hemangioma)

CaseHPOFreeText: retinal capillary hemangioma of the right eye

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: p.V241D

CaseProblemVariantFreeText: Variant determined through the assumption of the authors using Latif et al 1993 (AF010238.1) transcript and adding 71bp to the protein sequence.

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A