15 Dutch VHL patients from 5 families were taken to measure the expression of vascular endothelial growth factor (VEGF). Nine patients were found to harbour the VHL germline mutation V170D, referred to in the paper by V241D due to a difference in transcript sequence. Patient 1, a 57 year old female, presented with pancreatic cysts. Patient 4, a 31 year old male, presented with a kidney cyst and a brain hemangioblastoma and no signs of eye lesions. Patient 5, a 28 year old female, presented with a kidney cyst, brain hemangioblastoma, renal cell carcinoma and a left eye angioma. Patient 7, a 28 year old female, presented with a kidney cyst and a right eye angioma. Patient 8, a 28 year old female, presented with pancreatic cysts and a right eye angioma. Patient 9, a 61 year old male, presented with pancreatic and liver cysts, a brain hemangioblastoma and a left eye angioma. Patient 11, a 38 year old male, presented with pancreatic, liver and kidney cysts, brain and spinal cord hemangioblastomas and a right eye angioma. Patient 12, a 50 year old male, presented with kidney & pancreatic cysts, a pheochromocytoma and a brain hemangioblastoma as well as no sign of eye lesions. Patient 13, a 34 year old male, presented with pancreatic cysts, brain and spinal cord hemangioblastomas and right and left eye angiomas. ACMG: 'PP1' since we have cosegregation with the disease in multiple affected family members, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

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

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