PatientID: V209

KindredID: V209

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 5

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease.

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 21 and a multiple pancreatic cysts/tumors at age 30.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 52CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 52CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL familywith RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 64Y0M, Japanese

DiseaseAssertion: VHL

FamilyInfo: Her father was killed in an accident when she was young. Her older brother died of renal cell carcinoma associated with VHL disease at the age of 58. Her younger sister was also diagnosed with renal cell carcinoma that was associated with VHL disease. No members past the proband had been genetically tested.

CasePresentingHPOs: HP:0006880; HP:0030078; HP:0005584; HP:0001737 (cerebellar hemangioblastoma; lung adenocarcinoma; renal cell carcinoma; pancreatic cysts)

CaseHPOFreeText: of a hemangioblastoma of the cerebellum when she was 37 years old. Her right kidney was resected because of renal cell carcinoma at the age of 59. Concurrently, she received a pancreatojejunostomy for a pancreatic cyst. At the age of 63, radiofrequency ablation was performed for renal cell carcinoma of her left kidney. In the same year, computed tomography screening of the patient’s lungs detected nodules in the right middle lobe and left upper division. A computed tomography–guided needle biopsy of the nodule in the right middle lobe resulted in a diagnosis of adenocarcinoma (Fig 1). We concurrently performed a lobectomy of the patient’s right middle lobe and a partial resection of the left upper division.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: Loss of heterozygosity (LOH) at the VHL locus was detected in the lung adenocarcinoma. The hepatic adenocarcinoma was found with somatic EGFR mutations and loss of heterozygosity at the VHL locus; authors speculate that dysfunctional pVHL may promote mutations on the EGFR gene.

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: 1

GroupID/ KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.194C>T) was recorded in the paper as c.407C>T due to a difference in transcript sequence. It was found in one patient with hemangioblastomas of the central nervous system. No other phenotype described.

GroupID: 52

DiseaseAssertion: assumed VHL

GroupSize: 11

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 11 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.194C>T) was found in 4 VHL families with 11 patients altogether.

GroupPresentingHPOs: HP:0006880; HP:0005584; HP:0009711 (cerebellar hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

GroupHPOFreeText: 4 total patients had cerebellar hemangioblastoma; 2 had renal cell carcinoma; and 10 patients had retinal capillary hemangioma. Mean ages for each diagnosis follows: 25Y (RH), 43Y (CHB), 48Y (RCC).

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No patients had pheos

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65L (c.194C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: N/A (father)

KindredID: 1

Case: M, 43Y0M (deceased), Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The family medical history disclosed the presence of symptoms of VHLD in the patient’s daughter, brother, and father. His daughter was detected with the c.194C>T mutation in two of her tumors, likely germline with the familial relations. She also had undergone brain surgery at 23Y due to a cerebellar hemangioblastoma, and an ELST

CasePresentingHPOs: HP:0006880; HP:0005584 (cerebellar hemangioblastoma; Renal cell carcinoma)

CaseHPOFreeText: At the age of 30, he was operated on for cerebellar hemangioblastoma, and died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases 13 years later at the age of 43.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. Genotyping confirmation was performed by PCR-direct sequencing on peripheral blood samples. This mutation was confirmed in families #4, #5, and #5. Only the proband of family #4 (male, patient #7) was genetically confirmed with the mutation. He was diagnosed with renal cell carcinoma and multiple pancreatic cysts/tumors at age 33. Only the proband of family #5 was genetically confirmed with the mutation. He presented with a CNS hemangioblastoma at age 21 and multiple pancreatic cysts and tumors at age 30. His grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease. Family #6 is large: the proband (F, renal cell carcinoma at age 36 and pheochromocytoma at age 37) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13 (asymptomatic,) 14 (CNS hemangioblastoma at age 59,) 15 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19 (asymptomatic), 20 (asymptomatic), 21 (CNS hemangioblastoma and retinal angioma at 53,) and 22 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16 (CNS hemangioblastoma at 22) and 17 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).