PatientID: IP (Proband)

KindredID: E

Case: M, 21Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Index patient was a 21-year-old man who had bilateral renal masses and renal cysts. Family history indicated a high suspicion for VHL disease, as his mother was operated for renal cell carcinoma, his uncle had spinal cord tumor, and his grandmother underwent operation for renal cell carcinoma. However, detailed clinical evaluation could not be performed in family members.

CasePresentingHPOs: HP:0005584; HP:0005562 (Renal cell carcinoma, Multiple renal cysts)

CaseHPOFreeText: Presented with bilateral highly vascularized renal masses and a large number of renal cysts. Diagnosed with VHL Type 1. Renal masses are noted as renal cell carcinoma in Table 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119Qfs*12 (c.354_355del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA915940709, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.354_355del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: F119fs (c.354_355del)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: ASP (R167G)

Case: F, 20Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Mutation was absent in mother and two brothers. Proband of this family presented with an apparently sporadic pheochromocytoma and the R167G germline mutation of the VHL gene.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Presented with an apparently sporadic unilateral pheochromocytoma. VHL phenotype noted as type 2C.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Clinical evaluation of the three patients indicated the absence of other VHL-related tumors.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167G (c.499C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2219, https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

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

VariantEvidence: Variant reported as R167G and cDNA change was mapped to c.499C>G.

MutationType: missense_variant;transversion

CivicName: R167G (c.499C>G)

MultipleGeneVariants: N/A

PatientID: None (daughter)

KindredID: 1

Case: F, 5Y0M, ethnicity unknown

DiseaseAssertion: asymptomatic

FamilyInfo: The patient's family members (grandparents, mother (33Y0M; Case 1) and sister (10Y0M) underwent genetic testing. Sister and grandparents were not positive, however mother was found positive with the same mutation.

CasePresentingHPOs: None

CaseHPOFreeText: Full evaluation did not reveal any tumor localization.

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: N/A

MutationType: missense_variant;transition

CivicName: D92G (c.275A>G)

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

GroupID: 53

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.407T>C germline variant of the VHL gene. Members 939 and 1460 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:0005584 (Renal cell carcinoma)

GroupHPOFreeText: 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 2 and 2 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. One or both of these previously reported patients could correspond to family 94 in the current paper.

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

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064, https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

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/ KindredID: F31

Case: Sex unknown, 19Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

CasePresentingHPOs: HP:0009711; HP:0009713; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Age of onset is 19Y0M.

CaseNotHPOs: HP:0006770;HP:0002666 (clear cell renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Efs*6 (c.377_378insG)

LegacyVariant: g.5429_5430insG

CaseProblemVariantFreeText: Patient was reported with the g. (genomic) coding positions. The g.5429_5430insG variant worked out to correspond with c.377_378insG.

ClinVarID: N/A

CAID: CA2499307020 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307020

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: D126fs* (c.377_378insG)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 19

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient had VHL disease type 1 (see table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9829911

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

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: Variant reported as c.226_228del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 6

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: Transmission of the variant could not be determined since family history is not available. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient had Unilateral, Benign, Adrenal PH (see table 1)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9663592

SupplementalData:  N/A

Variant: p.L63P (c.188T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L63P (c.188T>C)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 17

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0006880; HP:0011513; HP:0001737; HP:0000107; HP:0006770 (Cerebellar hemangioblastoma, retinal cavernous angioma, pancreatic cyst, renal cyst, clear cell renal cell carcinoma)

CaseHPOFreeText: Patient had VHL disease type 1: CNS-HB, RA, ccRCC, PC, KCy, and parental mosaicism (see table 1). Previously published 2000 paper (106311387) reports patient as a 48Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10631138

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

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: Variant reported as c.226_228del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: III-6

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: CNS Hemangioblastoma

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 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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: N/A

MutationType: missense_variant;transversion

CivicName: S168T (c.503G>C)

MultipleGeneVariants: N/A

PatientID: 17

KindredID: 6007

Case: F, 31Y9M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with 1 radiographic pancreatic neuroendocrine tumor diagnosed at age 29Y. Follow up 33M after WP surgery, currently no evidence of disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

LegacyVariant: p.delF (c.439_441delTTC)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: 30

KindredID: 3407

Case: M, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 31) presented with one radiologic pancreatic neuroendocrine tumor and had the same VHL gene mutation.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with one radiologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (c.712C>T)

CaseProblemVariantFreeText: N/A

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

CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 43

KindredID: 5959

Case: F, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: p.P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVar: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: CA020148 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.241C%3ET

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: Germline, VHL, c.562C>G (p.Leu88Val)

PatientID: 30

KindredID: 30

Case: Age, sex, ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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) AND L89P (c.266T>A)

MultipleGeneVariants: Somatic, VHL, c.266T>A (p.Leu89Pro)

PatientID: 50

KindredID: 50

Case: Age, sex, ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Qfs*11 (c.477_478insCA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA645525053 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.477_478insCA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: K159fs (c.477_478insCA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 9

Case: F, 22Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668 (pheochromocytoma, paraganglioma)

CaseHPOFreeText: Sympathetic PGL with an onset of 11Y0M and a benign bilateral pheochromocytoma at 22Y0M

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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: 8

Case: M, 15Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma; paraganglioma; retinal capillary hemangioma)

CaseHPOFreeText: Benign sympathetic Paraganglioma at age 12Y0M and unilateral pheochromocytoma at age 15Y0M; as well as retinal angioma (age unclear)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y98S (c.293A>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her father had this VHL mutation and presented with renal cell carcinoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: She is described as affected but her phenotypes are not outlined.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: He had a daughter who has heterozygous for the mutation.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 1.7%. The right renal cell carcinoma was analyzed and found to have a mutated allele frequency of 11.1%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: III-46

KindredID: 1

Case: F, Age unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. Her sister, dad and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: None

CaseHPOFreeText: VHL found by genetic testing not clinical findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

PatientID: III-24

KindredID: 1

Case: F, Age unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. 1/2 of her sons also appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0002011; HP:0009711; HP:0000077 (Morphological central nervous system abnormality, retinal capillary hemangioma; Abnormality of the kidney)

CaseHPOFreeText: Patient mentioned to have CNS (including retinal angiomas) and renal involvement.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

PatientID: 422

KindredID: 422

Case: Sex Unknown, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0009711; HP:0006770; HP:0002666; HP:0001732; HP:0000107 (Retinal capillary hemangioma, Clear cell renal cell carcinoma, Pheochromocytoma, Abnormality of the pancreas, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17024664

SupplementalData: Table S1, S2 and S3

Variant: p.L135Yfs*24 (c.404del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421852, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: L135fs (c.404del)

MultipleGeneVariants: N/A

PatientID: 223

KindredID: 223

Case: Sex Unknown, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive family history for VHL.

CasePresentingHPOs: HP:0000107, HP:0010797 (renal cyst, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001737, HP:0002666, HP:0006770, HP:0009711 (pancreatic cysts, pheochromocytoma, clear cell renal cell carcinoma, retinal capillary hemangioma )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

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

GroupID/ KindredID: 6CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 6CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with 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.S183* (c.548C>A)

LegacyVariant: p.S183* (c.761C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site either by truncating the protein or by location between codons 157 and 189.

MutationType: stop_gained

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 11YO

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 Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 11YO. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with 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.C162Y (c.485G>A)

LegacyVariant: p.C162Y (c.698G>A)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 133CA

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 133CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with 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.G114C (c.340G>T)

LegacyVariant: p.G114C (c.553G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751376 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G>T

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4479NCI, 50CE

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 National Cancer Institute database as well as the Munich, university of Freiburg and Institude of Pathology database, with an unknown number of members belonging to Family ID 4479NCI and 50CE. 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 families with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8707293

SupplementalData: N/A

Variant: p.E70* (c.208G>T)

LegacyVariant: p.E70* (c.421G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 428806 https://www.ncbi.nlm.nih.gov/clinvar/variation/428806/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: E70* (c.208G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 43CA

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 43CA. 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 families with 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.V66* (c.196delG)

LegacyVariant: p.V66* (c.409delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432536396 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.196delG

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: V66* (c.196delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 42CE, 3618NCI

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 two databases: the Munich, university of Freiburg and Institute of Pathology database and the National Cancer Institute database. There was an unknown number of members belonging to Family IDs: 42CE and 3618NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 10458336; 7728151

SupplementalData: N/A

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

LegacyVariant: p.C162W (c.699C>G)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 16BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 16BMS. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with 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.G93Afs*66 (c.277delG)

LegacyVariant: FS (c.490delG)

CaseProblemVariantFreeText: NM_000551.3:c.277delG automaps to NM_000551.3:c.278delG due to redundancy

ClinVarID: 428811 https://www.ncbi.nlm.nih.gov/clinvar/variation/428811/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: G93fs (c.277delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 2547NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 2547NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

LegacyVariant: p.G93D (c.491G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 496054 https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: Neuroendocrine neoplasm (pheochromocytoma or paraganglioma)

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Ethnicity unknown

GroupAgeRange: N/A

GroupInfo: This mutation (p.Y156C (c.467A>G)) was found in 7 patients, 3 with a family history and/or a syndromic presentation and 4 with apparently sporadic presentation. 1 of the apparently sporadic patients was previously reported.

GroupPresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

GroupHPOFreeText: Patients with a pheochromocytoma or a functional paraganglioma were recruited from several different French clinical centers participating in several clinical research networks (Cortico et Medullosurrènale: les Tumeurs Endocrines, Paragan-Glioma Network, Groupe des Tumeurs Endocrines)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 1 of the apparently sporadic patients was previously reported.

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

GroupID: 25B

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 patients with the given mutation were grouped as group 25(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

GroupID: 23A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163H (c.488T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756137 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L163H (c.488T>A)

MultipleGeneVariants: N/A

GroupID: 24B

DiseaseAssertion: Unknown. Patients were pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 15

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 15 patients with the given mutation were grouped as group 24(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 28B

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation were grouped as group 28(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428794 https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: CA70052558 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.583C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

MultipleGeneVariants: N/A

GroupID: 12B

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET- Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A122I (c.364_365delinsAT)

LegacyVariant: N/A

CaseProblemVariantFreeText: Authors report this as: c.364_365GC>AT; which can be translated to c.364_365delinsAT

ClinVarID: N/A

CAID: CA658820874 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.364_365delinsAT

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: A122I (c.364_365delinsAT)

MultipleGeneVariants: N/A

PatientID: 87

KindredID: 27

Case: F, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 81) had 3 family members confirmed with the mutation: his aunt 2 (patient 85) had pancreatic cysts and/or tumors at age 50, his cousin/ the son of Aunt 2 was asymptomatic at the time of assessment, and the granddaughter of aunt 2 was also asymptomatic at the time of assessment. The proband also had 3 family members who passed away before diagnosis/ before confirming the mutation: his mother (patient 82) had a CNS hemangioblastoma at 33, his Aunt 1 (patient 83) had a CNS hemangioblastoma at 32, and his cousin/ the son of Aunt 1 (patient 84) had a CNS hemangioblastoma at 30.

CasePresentingHPOs: N/A

CaseHPOFreeText: The granddaughter of the proband's aunt 2 was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.N90I (c.269A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223172; https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: 50

KindredID: 17

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The proband presented with multiple pancreatic cysts/tumors and renal cell carcinoma at 30.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.L85P (c.254T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 376222; https://www.ncbi.nlm.nih.gov/clinvar/variation/376222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L85P (c.254T>C)

MultipleGeneVariants: N/A

PatientID: 131

KindredID: 49

Case: F, Age 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0005584; HP:0001737; HP:0001732; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The proband presented with a pheochromocytoma at 18, retinal angioma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 31.

CaseNotHPOs: HP:0010797 (Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.F136C (c.407T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065; https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 54

KindredID: 19

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 54) has a daughter who was genetically confirmed with the same mutation. The daughter was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 12, renal cell carcinoma and multiple pancreatic cysts/tumors at 33.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692; https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 231

KindredID: 86

Case: M, 54Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 229) had a sister (patient 230) who was genetically confirmed with the mutation, and presented with a CNS hemangioblastoma at age 40. The proband's brother 1 (patient 231) was also confirmed with the mutation and had a retinal angioma at 25, and renal cell carcinoma at 54. The proband's brother 2 passed away before they could be diagnosed/ confirmed with the mutation, but they had a CNS hemangioblastoma at 35. Finally, the proband's nephew (son of brother 2) was genetically confirmed with the mutation and presented with renal cell carcinoma at age 30.

CasePresentingHPOs: HP:0009711; HP:0005584 (Retinal capillary hemangioma, Renal cell carcinoma)

CaseHPOFreeText: The proband's brother (patient 231) had a retinal angioma at 25 and renal cell carcinoma at 54.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0001737; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.L178R (c.533T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625261, https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 6

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Family #6 is large. The proband (patient 12) 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/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's uncle's granddaughter (ie. the granddaughter of uncle 2), patient 19, was asymptomatic at the time of the study.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, 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: 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: 123

KindredID: 43

Case: M, Age 60Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The proband's father (patient 123) presented with a CNS hemangioblastoma at age 27, renal cell carcinoma at age 48, and multiple pancreatic cysts/tumors at age 60.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/AcDNAposition:349

PatientID: 189

KindredID: 72

Case: F, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 39, and multiple pancreatic cysts/tumors at 36.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.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

PatientID: 139

KindredID: 52

Case: F, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

CasePresentingHPOs:

CaseHPOFreeText: The proband's daughter was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0010797, HP:0001737; HP:0001732; HP:0005584; HP:0002666; HP:0009711 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 138

KindredID: 52

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

CasePresentingHPOs: HP:0010797, HP:0001737; HP:0001732; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The proband presented at age 28 with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 1 (tumour samples 1a, 1b, 1c)

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 42 CNS haemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient presented with 3 VHL-related tumors in the cerebellum (a,b,c). All three presented with LOH positive somatic information but negative methylation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

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

PatientID: None

KindredID: 1

Case: M, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: First cousin (male, 29Y, proband) presented with renal cell carcinoma, vitritis, retinal capillary hemangioma and retinal detachment. The proband also had the germline mutation found in his cousin.

CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0000648; HP:0000572 (Renal cell carcinoma, Hemangioblastoma, Retinal capillary hemangioma, Optic atrophy, Visual loss)

CaseHPOFreeText: He was operated on because of a CNS hemangioblastoma 3 years earlier. The patient stated that he had vision loss in his left eye after the CNS operation. About 2 weeks earlier, a partial right nephrectomy operation was performed due to RCC. The fundus examination revealed optic nerve atrophy and two RH (determined to be the cause of vision loss) at the equator in the left eye, and was normal in the right eye.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S68P (c.202T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621912, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA16621912

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S68P (c.202T>C)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 1

Case: Sex Unknown, 55Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma; retinal capillary hemangioma)

CaseHPOFreeText: 45Y at first pheochromocytoma and ocular angioma (retinal capillary hemangioma).

CaseNotHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 1

Case: Sex Unknown, 39Y0M, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584 (hemangioblastoma, pheochromocytoma; retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0030405 (pheochromocytoma, hemangioblastoma, pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

PatientID: 2

KindredID: 21

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL. One other family member mentioned (PatientID: 1)

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q195* (c.796C>T)

ClinVarID: 428794 https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: p.Q195* (c.583C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 48

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: one RCC tumor was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F76del (c.440delTCT)

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: LOH detected.

MutationType: deletion

CivicName: F76del (c.227delTCT)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 54

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: another member (54/2) of the family was detected with an HB and the same mutation

CasePresentingHPOs: HP:0006880 (hemangioblastoma)

CaseHPOFreeText: one RCC tumor was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177Dfs*25 (c.528delG)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.176 FS (c.741delG)

ClinVarID: N/A

CAID: CA432423454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.528delG

gnomAD: N/A

VariantEvidence: LOH detected.

MutationType: minus_1_frameshift_variant

CivicName: R177fs (c.528delG)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: P1

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: One other patient belonging to the same family (P1) had this mutation. They had 2 HB

CasePresentingHPOs: HP:0002666; HP:0006880 (pheochromocytoma, cerebellar hemangioblastoma)

CaseHPOFreeText: one pheochromocytoma and one cerebellar hemangioblastoma was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R167W (c.712C>T)

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

VariantEvidence: Tested the tumors for somatic mutations but did not detect any

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 52

KindredID: 2

Case: Sex Unknown, 23Y0M, Norwegian

DiseaseAssertion: pheochromocytoma

FamilyInfo: Yes, a family history of neuroendocrine tumor (NET). They have another family member with the same mutation and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Preoperatively presented with hypertension; surgery at 23Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: NF1, RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119S (c.356T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753715 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.356T%3EC

gnomAD: N/A

VariantEvidence: This mutation was found in DNA from the adjacent normal tissue, and this finding was found to be reproducible. The same VHL variant was later on observed in a family member with PHEO.

MutationType: missense_variant;transition

CivicName: F119S (c.356T>C)

MultipleGeneVariants: N/A

PatientID: VHL_6 (tumor ID)

KindredID: 6

Case: F, 31Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 31Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238, https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q164R (c.491A>G)

MultipleGeneVariants: N/A

PatientID: VHL_11 (tumour ID)

KindredID: 11

Case: F, 47Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal Pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at age 47.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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.500 G >A)

MultipleGeneVariants: N/A

PatientID: VHL_18 (tumor ID)

KindredID: 18

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at an unknown age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: Unknown

KindredID: 4

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 3 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: hemangioblastoma, parathyroid nodule, and esophageal carcinoma but the presenting patient is unclear. Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 25 years later but it is unclear if this pertained to all affected family members. VHL type 2C.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: III:8

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 5 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: paraganglioma, hemangioblastoma, lung metastases and spinal hemangioblastoma but the presenting patient is unclear.Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 18 years later but it is unclear if this pertained to all affected family members.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 7

Case: Sex Unknown, 29Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405 (paraganglioma, pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: The patient developed PPGL at 29Y of age, and a PNET at 29Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223201 https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 4

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patient 7,8,9,10).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405, HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient was diagnosed with pancreatic endocrine tumor at age 44 and diagnosed with pheochromocytoma and paraganglioma at age 18.

CaseNotHPOs: HP:0009711, HP:0001737, HP:0000107, HP:0005584 (retinal capillary hemangioma, pancreatic cysts, renal cyst, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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.500 G >A)

MultipleGeneVariants: N/A

PatientID: 13

KindredID: 6

Case: M, 22Y11M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 6, patient 12 was reported as having PPGL and PNETs at 36Y, along with renal and pancreatic cysts, and retinal HB. Their relation is not clear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient developed PPGL at 16Y of age. It was a right side Pheo measuring 1.7cm with no recurrence at follow up 83 Months after.

CaseNotHPOs: HP:0030405; HP:0010797; HP:0005584; HP:0001737; HP:0009711; HP:0000107 (pancreatic endocrine tumor, hemangioblastoma, renal cell carcinoma, pancreatic cyst, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 21

Case: Age unknown, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: Unknown

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0005584; HP:0002666; HP:0006880 (retinal capillary hemangioma; renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.T124Mfs*33 (c.371_377delCACACGA)

LegacyVariant: p.T124Mfs*33 (c.369_375delGACACAC)

CaseProblemVariantFreeText: written in paper as:c.369_375del, automaps to NM_000551.3:c.371_377del - most up to date transcript

ClinVarID: N/A

CAID: CA913189240 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.371_377delCACACGA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: G123fs (c.369_375delGACACAC)

MultipleGeneVariants: N/A

GroupID: 20

Case: 19Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: retinal capillary hemangioma

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: patient had retinal angiomas diagnosed at 19Y

CaseNotHPOs: HP:0005584; HP:0002666; HP:0006880 (renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.T124Hfs*35 (c.369delG)

LegacyVariant: p.Thr124Hisfs*35 (c.367delG)

CaseProblemVariantFreeText: c.367delG automaps to c.369delG - most up to date transcript

ClinVarID: N/A

CAID: CA432421810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.369delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: T124fs (c.369del)

MultipleGeneVariants: N/A

GroupID: 71

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.407T>C) was found in 2 VHL families with 5 patients altogether.

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

GroupHPOFreeText: 4 patients had cerebellar hemangioblastoma (CHB), 3 had renal cell carcinoma (RCC); and 3 had retinal capillary hemangioma (RH). Mean ages for each diagnosis follows: 25Y (RH), 43Y (CHB) and 41Y (RCC).

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.F136S (c.407T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID: 2

DiseaseAssertion: cerebellar hemangioblastoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.162_163insT) was found in 1 VHL family with 2 patients.

GroupPresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

GroupHPOFreeText: both patients had cerebellar hemangioblastomas with a mean age of diagnosis of 19Y

GroupNotHPOs: HP:0005584; HP:0009711; HP:0002666 (renal cell carcinoma; retinal capillary hemangioma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.E55* (c.162_163insT)

CaseProblemVariantFreeText: The mutation was written as follows: AFO10238:375_376insT; NM_000551.2:c.162_163insT; p.54MetX. Author Maher was contacted and confirmed "A single nucleotide insertion (T) was detected at position 375 (375insT)” from 2000 lab report - June 1, 2021 - therefore assume p. was transcribed incorrectly.

LegacyVariant: p.54MetX (c.375_376insT)

ClinVarID: N/A

CAID: CA2499307063 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307063

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: E55* (c.162_163insT)

MultipleGeneVariants: N/A

PatientID: 15

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 S5 describes 8 patients with small deletions, including this patient.

Variant: p.L129Wfs*30 (c.384del)

LegacyVariant: c.597delT (p.128fs)

CaseProblemVariantFreeText: Submitted revision on CIViC for correct CIViC name: L129Wfs*30 (c.384del).

ClinVarID: N/A

CAID: CA70049452

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: L129Wfs*?(c.383delT)

MultipleGeneVariants: N/A

PatientID: 44

KindredID: 44

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for VHL. No further details provided.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral pheochromocytoma. CNS hemangioblastoma. Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346; “Kim, J. W., Choi, S. J., Kim, Y. K., Ahn, S. M., Song, K. E., Jung, S. H. et al. A case report of von Hippel–Lindau disease manifested in a monozygous twin. J. Korean Soc. Endocrinol. 20, 395–400 (2005)” (Reference 15 in current publication).

SupplementalData: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: Proband 3

KindredID: 1

Case: M, 17Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral PCC diagnosed at 17Y and did not have any other clinical presentations. Stated as having VHL type IIC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

PatientID: Proband 6

KindredID: 2

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Mother, aunt and aunt’s cousin (all relative to proband 6) had this variant. Mother and proband presented with unilateral pheochromocytoma and aunt and aunt’s cousin were asymptomatic. Proband also presented with a renal cyst and hypertension.

CasePresentingHPOs: HP:0002666; HP:0000107; HP:0000822 (Pheochromocytoma, Renal cyst, Hypertension)

CaseHPOFreeText: Unilateral PCC diagnosed at 28Y and unilateral renal cyst and hypertension. Stated as having VHL type IIC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R120T (c.359G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753738, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.359G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R120T (c.359G>C)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 3

Case: F, 18Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Another member of this family (Gen 1) presented with the same mutation and bilateral pheochromocytoma, pancreatic cysts, RCC and neural hemangioblastoma.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0002668; HP:0030405; HP:0001737 (Pheochromocytoma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor, Pancreatic cysts)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Cause of death: adrenal crisis.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 146

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

Variant: p.W117C (c.351G>T)

LegacyVariant: c.564G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 167827, https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

GroupID: 53

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.194C>G variant causing a Ser65Trp missense mutation (noted in the paper as c.407C>G due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: This family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

LegacyVariant: p.S65W (c.407C>G)

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

GroupID: 141

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.490C>T variant causing a p.Gln164* stopgain (noted in the paper as c.703C>T due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: This family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164* (c.490C>T)

LegacyVariant: p.Q164* (c.703C>T)

ClinVarID: 223228 https://www.ncbi.nlm.nih.gov/clinvar/variation/223228/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q164* (c.490C>T)

MultipleGeneVariants: N/A