PatientID: 1

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her two sons and her father had the same VHL mutation.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: HP:0001737, HP:0002666, HP:0030393, HP:0009713 (pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, spinal hemangioblastoma)

CaseHPOFreeText: She presented with pancreatic cysts and pheochromocytoma at age 32. She experienced headache and dizziness and a temporal bone mass consistent with an ELS tumor was found on brain MR imaging. A preoperative audiogram showed no hearing function and she underwent a left transcochlear approach and resection of the tumor. The pathological diagnosis was consistent with an ELS tumor. She was later found to have a spinal hemangioblastoma that was resected and included in this study.

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

PatientID: 2

KindredID: 2

Case: F, 60Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0030405; HP:0006770; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, pancreatic endocrine tumour, clear cell renal cell carcinoma, pancreatic cysts, pheochromocytoma)

CaseHPOFreeText: patient was recorded with the above stated manifestations. Pancreatic cysts and pheochromocytomas were taken from PMID 23913169 (Gucer 2013)

CaseNotHPOs: HP:0030421 (epididymal tumour)

CaseNotHPOFreeText: patient was not recorded to have an epididymal tumor, a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm), CCRCC, nor a neuroendocrine neoplasm (pheochromocytoma/paraganglioma)

CasePreviousTesting: N/A

PreviouslyPublished: 23913169

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: c.464-1G>A

CaseProblemVariantFreeText: N/A

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

MultipleGeneVariants: N/A

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. Renal cell carcinoma occurred predominantly in non-missense mutations predicted to lead to gross alteration or complete loss of the VHL protein. This splice site mutation, c.464-1G>A (stated as 677-1G>A in the paper which used the Latif sequence as reference) was found in a VHL type 1 patient with retinal angiomas, pancreatic cysts, and renal cell carcinoma (family ID 68). This study contains very strong evidence for pathogenicity in the form of a -1 splice-site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

PatientID: 38

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 describes 9 patients with splice site mutations, including this patient.

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

MultipleGeneVariants: N/A

Of 65 VHL families from central Europe, 53 were identified with germline mutations. The mutation of c.464-1G>A was referred to in the paper by c.677-1G>A due to a difference in transcript sequence. This splice mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 48). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. This splice site variant, c.464-1G>A, was found in a 15-year-old VHL patient with retinal hemangioblastomas (index case 227). The patient did not have hemangioblastoma, pancreatic cyst, pheochromocytoma, clear cell renal cell carcinoma, renal cysts. This study contains very strong evidence for pathogenicity in the form of a splice site variant in a gene where loss-of-function is a known mechanism of disease.

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

Two unrelated patients were screened for VHL mutations using SSCP and sequence analysis. Patient W was found with a germline splice site variant mutation c.464-1G>A (stated as 677-1G>A in the paper which used the Latif sequence as reference). They had no prior family history but parents were not available for genetic testing. The patient had hemangioblastoma and renal cell carcinoma.

Of 65 VHL families from central Europe, 53 were identified with germline mutations, using SSCP analysis of PCR products by peripheral blood. The mutation of c.464-1G>A was referred to in the paper by c.677-1G>A due to a difference in transcript sequence. This splice mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 48). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

GroupID/ KindredID: VHL 48

Case: Sex unknown, Age unknown, German

DiseaseAssertion: assumed VHL

FamilyInfo: One patient with the given mutation is stated to belong to VHL family 48

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: c.677-1G>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: Splice Site (c.464-1G>A)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 describes 9 patients with splice site mutations, including this patient.

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

MultipleGeneVariants: N/A

PatientID: 147

KindredID: 53

Case: F, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother presented with a CNS hemangioblastoma at age 17. She passed away before she could be diagnosed/ genetically confirmed with the same mutation as her daughter.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 18.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

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: c.464-1G>A

LegacyVariant: N/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: Splice Site (c.464-1G>A)

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