GroupID: 285

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family are reported as carrying the E52K (c.154G>A) germline variant of the VHL gene. Member 6493 had no renal involvement, member 1422 had mild renal involvement and member 6495 had moderate renal involvement (RCC) and member 6497 phenotypes were unknown. 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: N/A

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

Variant: p.E52K (c.154G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 161402, https://www.ncbi.nlm.nih.gov/clinvar/variation/161402/

CAID: N/A

gnomAD: 0.00008525, https://gnomad.broadinstitute.org/variant/3-10183685-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E52K (c.154G>A)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family presented with the c.525C>A germline variant of the VHL gene. Members 6548 and 6362 had unknown renal involvement. Member 6364 presented with mild renal disease. Member 6728 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, where 1 individual with this mutation is reported. It is unclear which of the current family members the previously published individual corresponds to.

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

Variant: p.Y175* (c.525C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1298905, https://www.ncbi.nlm.nih.gov/clinvar/variation/1298905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y175* (c.525C>A)

MultipleGeneVariants: N/A

GroupID: 60

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe 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]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

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 individuals and 3 families 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. These previously published individuals could alternatively correspond to family 279.

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

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 5299

KindredID: 235

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 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.

CasePresentingHPOs: HP:0009726 (Renal neoplasm)

CaseHPOFreeText: 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]). Individual RCC phenotype is noted as negative.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with an equivalent mutation (i.e. 473insT) 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.K159Efs*15 (c.473dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423097, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.473dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: K159Efs*15 (c.473dup)

MultipleGeneVariants: N/A

GroupID: 17

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family presented with the c.485G>A germline variant of the VHL gene. Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease. 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]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.C162Y (c.485G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

GroupID: 77

DiseaseAssertion: VHL

GroupSize: 13

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 13 members of this family were found to harbor the c.286C>T germline variant of the VHL gene. Members 5314, 6288, 6290, 5228 and 2499 had unknown renal involvement. Patients 5226, 6293 and 5340 presented with severe renal disease (RCC). Member 666 and 5223 presented with moderate renal disease (RCC). Members 5808 and 6380 had no renal involvement. Member 6277 presented with mild 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). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 3 individuals with this mutation are reported but relation between patients and to this patient is unknown.

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

Variant: p.Q96* (c.286C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 33Y0M, ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The patient's family members (parents and 2 daughters aged 10 and 5 yr) underwent genetic testing. The same mutation was found in the youngest daughter, although full evaluation did not reveal any tumor localization.

CasePresentingHPOs: HP:0030393; HP:0000107; HP:0009726; HP:0001737; HP:0006880 (endolymphatic sac tumour; renal cyst; renal neoplasm; pancreatic cysts; cerebellar hemangioblastoma)

CaseHPOFreeText: hypotympanic mass was found behind a normal tympanic membrane. Audiometry revealed complete hearing loss of the right ear - CT and MRI revealed lysis of the posterior face of the petrous pyramid by a voluminous heterogenous mass invading the infralabyrinthine and retrolabyrinthine regionsand the posterior cranial fossa, and an infracentimetric hypervascular lesion in the right cerebellum highly suggestive of a hemangioblastoma. These findings evoked the diagnosis of ELST associated with VHL disease. Abdominal ultrasonography and MRI of the patient showed multiple pancreatic cysts but no renal or adrenal gland abnormalities. Regular medical follow-up 4 years after the discovery of the disease showed a right renal cyst and centimetric tumor of the left kidney.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D92G (c.275A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750765 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275A%3EG

gnomAD: N/A

VariantEvidence: Histopathology showed a low-grade papillary adenocarcinoma of the endolymphatic sac, with strong immunoreactivity for cytokeratin (KL1), vimentin, and neuron-specific enolase and low immunoreactivity for epithelial membrane antigen.

MutationType: missense_variant;transition

CivicName: D92G (c.275A>G)

MultipleGeneVariants: N/A

PatientID: V-1

KindredID: 1

Case: M, 46Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s grandmother and two uncles had died with cerebellar hemangioblastoma, although genetic testing was not performed. The patient’s father presented with cerebellar hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and serous cystadenoma at 68Y, adrenal pheochromocytoma at 73Y, and clear cell renal cell carcinoma metastasis in the thyroid at 74Y; he was found to carry the same mutation the patient carried. One of the patient’s sons, a 10Y male, was also found to carry the same mutation as the patient but was asymptomatic. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

CasePresentingHPOs: HP:0009726; HP:0000107; HP:0001737 (Renal tumour, renal cyst, pancreatic cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82P(c.245G>C)

LegacyVariant: N/A

ClinVarID: 193118, http://www.ncbi.nlm.nih.gov/clinvar/variation/193118

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P(c.245G>C)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts)

CaseHPOFreeText: Patient 4 was a 52-year-old female a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, retinal angioma, pancreatic cyst.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: c.446A>G

CaseProblemVariantFreeText: N/A

ClinVar: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA351749194

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S (c.223A>G)

MultipleGeneVariants: N/A

PatientID: 16

KindredID: 16

Case: F, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0010797 (Renal neoplasm, Hemangioblastoma)

CaseHPOFreeText: Patient 16 had genetic testing and was found to have a germline mutation c.286C>T (Gln96*).

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96* (c.286C>T)

LegacyVariant: c.499C>T

CaseProblemVariantFreeText: N/A

ClinVar: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: CA351750811

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

GroupID: 362

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.395A>C germline variant of the VHL gene. Member 8813 had unknown renal involvement. Member 5862 presented with mild renal disease. 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 (Renal neoplasm)

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]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 1 individual with this mutation is reported. It is unclear which of the members of this family this previously reported patient corresponds to.

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

Variant: p.Q132P (c.395A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496063, https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Q132P (c.395A>C)

MultipleGeneVariants: N/A

GroupID: 509

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to have the c.500G>A germline variant of the VHL gene. Member 11209 presented with mild renal disease (RCC), member 10939 had unknown renal involvement and members 10901 and 10902 had no renal involvement. 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:0005584 (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]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 13

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother of this patient was also found to harbor the c.436delC germline variant of the VHL gene and presented with spinal and cerebellar hemangioblastomas and multiple pancreatic cysts.

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584; HP:0009726 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma, Renal neoplasm)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, renal carcinoma and a renal tumor <3cm in size.

CaseNotHPOs: HP:0002894; HP:0002666 (Neoplasm of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P146Lfs*13 (c.436del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421892, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.436del

gnomAD: N/A

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

MutationType: deletion; minus_1_frameshift_variant

CivicName: P146fs (c.436del)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 38Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo:All patients from the German registry for VHL with PNETs >3 cm diameter with tumours located in the pancreatic body or tail region.

CasePresentingHPOs: HP:0009711, HP:0009713, HP:0006880, HP:0009726, HP:0030405, HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm, pancreatic endocrine tumour, pancreatic cysts)

CaseHPOFreeText: Retinal angiomatosis at age 17, hemangioblastoma of the cervical spinal cord at age 24, cerebellar hemangioblastoma at age 27, left renal tumor at age 36. Pancreatic endocrine tumour and pancreatic cysts at age 38. She had a laparoscopy which found an 8-cm retrogastric cyst, 3.2-cm benign PNET, and a serous cystadenoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q132* (c.394C>T)

MultipleGeneVariants: N/A

PatientID: P1

KindredID: 1

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s father, age 45, presented with right ccRCC and pancreatic cysts. The patient’s uncle, age 38, presented with unilateral ccRCC. Both the patient’s father and uncle were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0009726; HP:0001737 (Renal neoplasm, pancreatic cysts)

CaseHPOFreeText: The patient presented with two right renal masses and several pancreatic cysts at 22Y.

CaseNotHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: Full VHL phenotyping with brain and spine MRI, abdominal CT, biochemical examination for pheochromocytoma, and ophthalmologic assessments did not reveal any additional VHL manifestations.

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

PatientID: 13

KindredID: 13

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0010797 (Renal neoplasm,Multiple renal cysts, Hemangioblastoma)

CaseHPOFreeText: Patient 13 was a 48-year-old male with a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, CNS hemangioblastoma.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162W (c.486C>G)

LegacyVariant: c.699C>G

CaseProblemVariant Free Text: N/A

ClinVar: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: CA357016

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transversion

CivicName: C162W(c.486C>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; HP:0006770 (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts, Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient 2 was a 44-year-old female with a medical history of asynchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, retinal angioma, pancreatic cysts.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: c.446A>G

CaseProblemVariantFreeText: N/A

ClinVar: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA351749194

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S (c.223A>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0010797; HP:0001737; HP:0006770 (Renal neoplasm, Multiple renal cysts, Hemangioblastoma, Pancreatic cysts, Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient 7 had a medical history of a left solid renal tumor and multiple renal cysts. They also had central nervous system hemangioblastomas and pancreatic cysts.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.447del)

LegacyVariant: c.661delA

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: CA432421904, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.447del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.447del)

MultipleGeneVariants: N/A

GroupID: 287

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family are reported as carrying the c.197_220del24 germline variant of the VHL gene. Member 6396 presented with mild renal disease. Member 6611 presented with severe 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]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 9829912, where 1 patient with this mutation is reported but relation to this patient is unclear.

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

Variant: p.N67_V74del (c.197_221del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130203, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130203

gnomAD: N/A

VariantEvidence: Variant reported as c.197_220del and was mapped to c.198_221del.

MutationType: inframe_deletion; deletion

CivicName: N67_V74del (c.197_221del)

MultipleGeneVariants: N/A

GroupID: 233

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.393C>A germline variant of the VHL gene. Member 5114 had no renal involvement. Member 5112 presented with mild renal disease. 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 (Renal neoplasm)

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]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 9829912, where 1 individual with this mutation is reported. It is unclear which of the members of this family this previously reported patient corresponds to.

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

Variant: p.N131K (c.393C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 420074, https://www.ncbi.nlm.nih.gov/clinvar/variation/420074/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N131K (c.393C>A)

MultipleGeneVariants: N/A

GroupID: 1

DiseaseAssertion: VHL

GroupSize:14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 14 members of this family presented with the c.499C>T germline variant of the VHL gene. Members 296, 419, 295 and 414 had no renal involvement. Members 427, 318, 403 and 406 had unknown renal involvement. Members 402, 322, 403 and 1 had mild renal disease (RCC). Members 401 and 404 had 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 15 individuals and 3 families 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. These previously reported individuals/families could alternatively correspond to family 23 or 50.

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

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>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: 49

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with the c.496G>T germline variant of the VHL gene. Member 2046 had no renal involvement. Member 1258 presented with mild renal disease. 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 (Renal neoplasm)

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]).

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 2 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.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

GroupID: 333

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with the c.500G>A germline variant of the VHL gene. Member 9428 presented with mild renal disease. Member 13001 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 10 individuals and 3 families 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. These previously reported individuals/families could alternatively correspond to family 262, 36 or 509.

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

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 185

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family are reported as carrying the c.193T>C germline variant of the VHL gene. Member 9359 has unknown renal involvement. Member 9357 presented with mild renal disease. Member 1052 had no renal involvement. Member 3979 has 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, where 2 patients with this mutation are reported but relation between patients is unknown.

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

Variant: p.S65P (c.193T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 547829, https://www.ncbi.nlm.nih.gov/clinvar/variation/547829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65P (c.193T>C)

MultipleGeneVariants: N/A

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family were found to have the germline c.226_228del variant of the VHL gene. Member 4975 presented with moderate renal disease (RCC), members 4978, 4977 and 4976 presented with mild renal disease and member 5283 had unknown renal involvement. 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

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

Variant: p.F76del (c.226_228del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: F76del (c.226_228del)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: The transversion mutation was found and confirmed in 4 patients (II-2, III-2, III-6, III-10, III-11) and 3 carriers (III-3, III-9, III-14). At least 5 additional members had VHL phenotypes, but had all passed away before genetic testing. Could be assumed and deduced their genetics due to pedigree showing future linear relations of this mutation all in generation III.

CasePresentingHPOs: HP:0010797; HP:0009726 (hemangioblastoma; renal neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168T (c.503G>C) [assumed]

LegacyVariant: p.S168T (c.716G>C) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.503G%3EC

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 39Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history. All 7 of his other family members (his parents, sister, son, sister’s son, brother, and brother’s son) were sequenced and no mutation were found. Additionally, all were healthy members. Suggestive of de novo due to no abnormal changes in the VHL gene of either parent.

CasePresentingHPOs: HP:0010797; HP:0009713; HP:0006880; HP:0009726 (hemangioblastoma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm)

CaseHPOFreeText: At 32Y this patient presented with progressive back and neck pain and numbness. Patient developed multiple CNS hemangioblastomas (multiple lesions in the cerebellum, brain stem, and spinal cord). Subsequent evaluation of the abdomen revealed a solid kidney tumor (visceral tumor).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No family history of VHL disease.

CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0002666; HP:0009726; HP:0001737 (endolymphatic sac tumor, retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal neoplasm, pancreatic cysts)

CaseHPOFreeText: patient was 21 years old when he experienced a sudden right hearing loss (cophosis). During a follow-up, the patient suffered from other manifestations of VHL disease mentioned above.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113*(c.337C>T)

MultipleGeneVariants: N/A