Analysis of peripheral blood samples from 5 Japanese families with PCR and SSCP revealed 4 germline mutations. This splice site mutation NM_000551.3:c.464-1G>T was found in a family of 10 individuals. Please note that the paper states the mutation as c.464-1G>T because it uses a legacy reference sequence. Three VHL patients were identified with hemangioblastomas of the central nervous system and retinal angiomas (family C). The eldest patient also had renal cell carcinoma (listed as C-1 in publication).

PatientID: 6

KindredID: 6

Case: F, 21Y6M, ethnicity unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Positive history, with symptomatic father (no mutation known)

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0001737; HP:0000107 (cerebellar hemangioblastoma; retinal capillary hemangioma; pancreatic cysts; renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: Compound heterozygous: Germline C to G base change at nucleotide 150 of exon 1, and G to T base change at -1 position of splice acceptor sequence for exon 3

MutationType: splice_site_variant

CivicName: [A50= (c.150C>G) and] Splice Site (c.463-1G>T)

MultipleGeneVariants: Germline, VHL, c.150C>G (p.Ala50Ala)

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The c.464-1G>T germline mutation of the VHL gene was found in a VHL type 1 family of 7. All seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, one had pancreatic cysts or tumor (unspecified), and 3 had renal cell carcinoma (family ID 3). This family was previously reported in PMID 8634692. ACMG codes as follows: A canonical -1 splice-site variant in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).

A retrospective study reviewed cases of 23 patients with advanced and complicated VHL eye disease who underwent pars plana vitrectomy in the years 1999 to 2012 that were a part of 223 VHL patients consulted at the International Hereditary Cancer Center and Polish VHL Registry. Genetic molecular analysis was performed in 22/23 patients through PCR and MLPA, and 24 eyes from 23 patients were studied. A 23 year old (patient 21) with a germline intronic mutation c.464-1G>T, stated in the paper as c.IVS2-1G>T, with previous history of HbCNS. Patient was examined in a study of advanced VHL eye disease and had multiple retinal capillary hemangioblastomas requiring surgery.

PatientID: 21

KindredID: 21

Case: 23Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioma)

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “IVS2-1G>T”

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

Direct sequencing and multiplex ligation dependent probe amplification were performed on thirteen unrelated subjects with VHL mutations. The clinical manifestations and family histories of the subjects were evaluated. A 38 year old Korean male patient presented with imbalance, gait disturbance and cerebellar hemangioblastoma, multiple pancreatic cysts and renal cysts. Genetic testing confirmed a splice mutation at c.464-1G > T of the VHL gene. Family history is unknown.

PatientID: None

KindredID: 8

Case: M, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0000107; HP:0002172; HP:0001288 (Cerebellar hemangioblastoma, Pancreatic cysts, Renal cyst, Postural instability, Gait disturbance)

CaseHPOFreeText: At 38Y, this patient showed mild imbalance with gait difficulty. MRI of the brain revealed a cystic mass in the cerebellum, which was pathologically found to be hemangioblastoma. When this patient underwent CT, which included the pancreas and kidney, multiple pancreatic cysts and renal cysts were found. Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223221, https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transversion

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

MultipleGeneVariants: N/A

PatientID: ccRCC-132

KindredID: 132

Case: M, 59Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

CohortInfo: 240 ccRCC specimens.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText:He was diagnosed with ccRCC at age 54.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary table 1.

Variant: c.464-1G>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: ccRCC-159

KindredID: 159

Case: M, 59Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

CohortInfo: 240 ccRCC specimens.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText:He was diagnosed with ccRCC at age 56.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary table 1.

Variant: c.464-1G>T

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 8

KindredID: C

Case: M, Age Unknown, Japanese

DiseaseAssertion: Asymptomatic

FamilyInfo: This mutation was found in a family of 10 individuals; six were found to carry the mutation NM_000551.3:c.464-1G>T the patient carried, and three presented with symptoms. They were identified with hemangioblastomas of the central nervous system and retinal angiomas. The eldest patient also had renal cell carcinoma (patient C-1).

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>T)

LegacyVariant: (c.677-1G>T)

ClinVarID: 223221, http://www.ncbi.nlm.nih.gov/clinvar/variation/223221

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: SpliceSite(c.464-1G>T)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: C

Case: M, Age Unknown, Japanese

DiseaseAssertion: Asymptomatic

FamilyInfo: This mutation was found in a family of 10 individuals; six were found to carry the mutation NM_000551.3:c.464-1G>T the patient carried, and three presented with symptoms. They were identified with hemangioblastomas of the central nervous system and retinal angiomas. The eldest patient also had renal cell carcinoma (patient C-1).

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states this case was not yet symptomatic, suggesting they may be too young to show symptoms yet

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.464-1G>T)

LegacyVariant: (c.677-1G>T)

ClinVarID: 223221, http://www.ncbi.nlm.nih.gov/clinvar/variation/223221

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: SpliceSite(c.464-1G>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: C

Case: M, Age Unknown, Japanese

DiseaseAssertion: Asymptomatic

FamilyInfo: This mutation was found in a family of 10 individuals; six were found to carry the mutation NM_000551.3:c.464-1G>T the patient carried, and three presented with symptoms. They were identified with hemangioblastomas of the central nervous system and retinal angiomas. The eldest patient also had renal cell carcinoma (patient C-1).

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that this patient was not yet symptomatic, suggesting they may be too young to show symptoms yet.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.464-1G>T)

LegacyVariant: (c.677-1G>T)

ClinVarID: 223221, http://www.ncbi.nlm.nih.gov/clinvar/variation/223221

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: SpliceSite(c.464-1G>T)

MultipleGeneVariants: N/A