PatientID: 10

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 S1 describes 19 patients with missense mutations, including this patient.

Variant: p.V130F(c.388G>T)

LegacyVariant: c.601G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130F(c.388G>T)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: IV

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None - considered VHL Type 1 due to the absence of pheochromocytoma and presence of pancreatic tumors.

CasePresentingHPOs: HP:0010797; HP:0002894 (hemangioblastoma; neoplasm of the pancreas)

CaseHPOFreeText: Patient had a CNS hemangioblastoma and a pancreatic tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130F (c.388G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V130F (c.601G>T)

ClinVarID: 496061 https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: Refer to table 3 for LOH information on VHL and ZAC1, and elongin-binding.

MutationType: missense_variant; transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: F2

Case: Sex unknown, 26Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: None. Microsatellite analysis excluded nonpaternity for this patient, leading to the assumption that this variant was de novo in character. (assumed de novo without confirmation of maternity).

CasePresentingHPOs: HP:0006880; HP:0001737 (cerebellar hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: cerebellar hemangioblastoma had multiple lesions. Age of onset is 26Y0M.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0009711 (clear cell renal cell carcinoma, pheochromocytoma, renal cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 8Y0M, Ethnicity Unknown

DiseaseAssertion: endolymphatic sac tumor (ELST)

FamilyInfo: N/A

CasePresentingHPOs: HP:0030393 (endolymphatic sac tumor)

CaseHPOFreeText: ELST that occurred in the left temporal bone who presented with profound sensorineural hearing loss, intermittent vertigo. A CT demonstrated a destructive mass involving the posterior aspect of the left petrous temporal bone centered midway between the internal auditory canal and the sigmoid sinus. Bony erosion extends into the posterior semicircular canal, and there are areas of stippling and central calcification within the mass suggestive of an aggressive, erosive process

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: c.601G>C mutation in the vHL gene on chromosome 3

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: I

KindredID: 2

Case: Sex Unknown, 1Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: One other family member presented with his VHL mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 0Y. Age at the end of study: 1Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130I (c.388G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753916, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

GroupID: 33

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: N/A

GroupHPOFreeText: These 2 patients with a c.388G>A mutation did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130I (c.388G>A)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753916 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G>A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 14

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0100634 (hemangioblastoma; clear cell renal cell carcinoma; Neuroendocrine neoplasm)

CaseHPOFreeText: patient had CNS hemangioblastoma, ccRCC and a neuroendocrine neoplasm reported as pheochromocytoma/paraganglioma.

CaseNotHPOs: HP:0030405; HP:0009711; HP:0030421 (pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.V130Wfs*30 (c.385_386dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: p.Leu128fs (c.385_386dupCT) does not verify. Contacted authors for clarification and confirmation of c.385_386dup; p.Val130Trpfs*30 as the correct mutation

ClinVarID: N/A

CAID: CA2573130306 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.385_386dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: V130Wfs*30 (c.385_386dup)

MultipleGeneVariants: N/A

GroupID/ KindredID: 10

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 registrants belonging to the same family (10) have the germline VHL mutation.

GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0000107 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst)

GroupHPOFreeText: 4 had retinal hemangioblastomas, 3 had CNS hemangioblastomas, 2 had renal cell carcinoma, with 4 renal cysts and 3 had pancreatic cysts

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

Variant: p.V130F (c.388G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496061 https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 7

Case: Unknown, 31Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0002666 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, pheochromocytoma)

CaseHPOFreeText:The patient presented with hemangioblastoma and pheochromocytoma at age 30. One year later he was found to have renal cell carcinoma and pancreatic cysts or tumors.

CaseNotHPOs: HP:0009711(retinal capillary hemangioma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: VHL

Group size: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this pedigree, 6 individuals were suspected of VHL disease. 5/6 individuals developed RH, while 1/6 did not.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 5/6 patients in this family with VHL disease presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.V130P (c.388G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10188245G>T

MutationType: missense_variant; transversion

CivicName: V130P (c.388G>T)

MultipleGeneVariants: N/A

GroupID: 91

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to harbor the c.388G>C germline variant of the VHL gene. Member 6200 had no renal involvement. Member 6410 presented with mild renal disease. Members 5838 and 5839 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229, https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 14 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0002894; HP:0009711; HP:0010797; HP:0005584 (Neoplasm of the pancreas, Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)

GroupHPOFreeText: CNS hemangioblastoma (7/14 affected members), renal carcinoma (1/14 affected members) and retinal angioma (2/14 affected members) and pancreatic cystadenoma (number of affected individuals not specified).

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130F (c.388G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: missense_variant;transversion

CivicName: V130F (c.388G>T)

MultipleGeneVariants: N/A