GroupID/ KindredID: 15

DiseaseAssertion: pheochromocytoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 patients are listed with this mutation; any relation is unknown. This mutation was said to be spontaneous.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: 2 members are stated to have pheochromocytoma. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161Q (c.695G>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: N/A

KindredID: 16

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161P (c.482G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161P (c.695G>C)

ClinVarID: N/A

CAID: CA351756111 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.482G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R161P (c.482G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 7

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Croatian

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation belonging to VHL family 7

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

GroupHPOFreeText: all 3 patients has retinal capillary hemangiomas, but only 1 tally of hemangioblastomas of the central nervous system, renal cysts, and pancreatic cysts were listed.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+2T>C

CaseProblemVariantFreeText: The mutation was referred to in the paper as c.676+2C>T - which was corrected to c.676+2T>C with a footnote indicating the correction in relation to Glavac et al Hum Mutat 1996.

LegacyVariant: c.676+2C>T (or correction of c.676+2T>C)

ClinVarID: 569414 https://www.ncbi.nlm.nih.gov/clinvar/variation/569414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.463+2T>C)

MultipleGeneVariants: N/A

PatientID: 220

KindredID: 82

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.

CasePresentingHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

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.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 81

KindredID: 27

Case: M, 38Y0M, 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: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0002666 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at age 28, and renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 38.

CaseNotHPOs: HP:0009711(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.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: 160

KindredID: 61

Case: M, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a renal cell carcinoma at age 44.

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

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.R161* (c.481C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 156

KindredID: 58

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband's sister presented with a CNS hemangioblastoma at 21, and multiple pancreatic cysts/tumors at 27.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711 (Pheochromocytoma, Renal cell carcinoma, 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.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 5

Case: M, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 21 and a multiple pancreatic cysts/tumors at age 30.

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

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: 97

KindredID: 33

Case: M, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseHPOFreeText: The proband, patient 291, presented with a CNS hemangioblastoma at 27, and at 31 presented with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

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.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

MultipleGeneVariants: N/A

PatientID: 213

KindredID: 80

Case: M, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's son and sister were both confirmed to have this VHL mutation. Their son had a retinal angioma at 26 and a pheochromocytoma at 31. Their sister had a pheochromocytoma at 14. Their mother had renal cell carcinoma at 56, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 52.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0002666; HP:0005584 (Retinal Capillary Hemangioma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, 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.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: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 10

Case: M, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 21) and his son were both confirmed with this mutation. His son was asymptomatic at the time of assessment.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's son (patient 29) was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0002666, HP:0009711; HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, 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.F76del (c.227_229del)

LegacyVariant: F76del (c.224_226delTCT)

CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

ClinVarID: N/A

CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 41

KindredID: 14

Case: F, 44Y0M, 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 renal cell carcinoma and multiple pancreatic cysts/ tumors at age 44.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal capillary hemangioma, 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.S80Ifs*79 (c.239del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239del)

MultipleGeneVariants: N/A

PatientID: 233

KindredID: 86

Case: M, 30Y0M, 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:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The proband's nephew (son of brother 2) (patient 233) had a renal cell carcinoma at age 30.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732; HP:0009711; HP:0010797 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, 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.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: 71

KindredID: 25

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband has the same mutation as her son (patient no.72). Her son did not present with hemangioblastoma, multiple pancreatic cysts/tumors, retinal angioma, renal cell carcinoma, or pheochromocytoma, and is apparently asymptomatic.

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

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 28, multiple pancreatic cysts/tumors at age 28, and hemangioblastoma at age 30.

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

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.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182978, https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 4 members are said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other member is specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

GroupID: 27

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 4 members are said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other 1 member is specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: 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: 38

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 1 member is said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other 2 members are specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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; transtition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

GroupID: 20

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.R108L*52 (c.322_323insTG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2501548609 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2501548609

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift

CivicName: R108fs (c.322_323insTG)

MultipleGeneVariants: N/A

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: all 3 patients were said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: 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

GroupID: 14A

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.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: M, 11Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with unilateral pheochromocytoma at 15Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238W(c.712C>T)

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

gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: F, 41Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: Of the patient’s three sons, two carried the mutation; one son presented with unilateral pheochromocytoma at 15Y, and another son presented with bilateral pheochromocytoma at 11Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 41Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238W(c.712C>T)

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

gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

GroupID: 3710

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 6 family members recorded with this mutation.

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

GroupHPOFreeText: all 6 members had CNS hemangioblastomas, 4/6 members had retinal angiomas (hemangiomas), and 3/6 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135* (c.404T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L206* (c.617T>A)

ClinVarID: N/A

CAID: CA351754021 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: L135* (c.404T>A)

MultipleGeneVariants: N/A

GroupID: 3708

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

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

GroupHPOFreeText: both (2) members has RCC and 1 member had hemangioblastoma

GroupNotHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L255P (c.764T>C)

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3509

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162R (c.484T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C233R (c.697T>C)

ClinVarID: 496067 https://www.ncbi.nlm.nih.gov/clinvar/variation/496067/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: C162R (c.484T>C)

MultipleGeneVariants: N/A

GroupID: 3616

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 4 family members recorded with this mutation.

GroupPresentingHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma, renal cell carcinoma)

GroupHPOFreeText: 2/4 members had retinal angiomas (hemangiomas), and 2/4 had RCC

GroupNotHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V155Cfs*4 (c.462delA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.225fs (c.675delA)

ClinVarID: 625251 https://www.ncbi.nlm.nih.gov/clinvar/variation/625251/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V155fs (c.462delA)

MultipleGeneVariants: N/A

PatientID: IV-2

KindredID: 1

Case: F, Age Unknown, Turkish

DiseaseAssertion: asymptomatic

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s father, sister, grandmother and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: None - described as a carrier of the p.A149S mutation, with no clinical manifestations. Their asymptomatic work up could have been due to the individual's young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: III-20

KindredID: 1

Case: M, 32Y0M, Turkish

DiseaseAssertion: VHL

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient likely inherited this from his father, and passed it onto his son. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: bilateral adrenal pheochromocytoma. He also had capsular invasion of his adrenal masses.

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 12BMS

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: Family 12BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65* (c.194C>A)

LegacyVariant: p.S65* (c.407C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223161 https://www.ncbi.nlm.nih.gov/clinvar/variation/223161/

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: S65* (c.194C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 113CA

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 Family 113CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as a VHL family without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E186del (c.558_560del)

LegacyVariant: delGlu (c.771_773delGlu)

CaseProblemVariantFreeText: N/A

ClinVarID: 625264 https://www.ncbi.nlm.nih.gov/clinvar/variation/625264/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: E186del (c.558_560delAGA)

MultipleGeneVariants: N/A

GroupID/ KindredID: 52CA

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 52CA. 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 familywith 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.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

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

GroupID/ KindredID: 4942NCI, 4422NCI, 2005F

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 multiple databases, including: the Neuro Olcologie database in Paris, and the National Cancer Institute database, with an unknown number of members belonging to three family IDs: Family ID 4942NCI, 4422NCI, and 2005F. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as 3 VHL families 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.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

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

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: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 39CE

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 39CE. 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.S80N (c.239G>A)

LegacyVariant: p.S80N (c.452G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 1070179 https://www.ncbi.nlm.nih.gov/clinvar/variation/1070179/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S80N (c.239G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 26CA

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 26CA. 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: N/A

SupplementalData: N/A

Variant: p.V170F (c.508G>T)

LegacyVariant: p.V170F (c.721G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756193 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.508G>T

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: V170F (c.508G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 51F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 51F. 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: N/A

SupplementalData: N/A

Variant: p.P192Qfs*10 (c.575delC)

LegacyVariant: FS (c.786delC)

CaseProblemVariantFreeText: NM_000551.3:c.573delC automaps to c.575delC

ClinVarID: N/A

CAID: CA432423729 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.575delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P192fs (c.575delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 8YO

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 8YO. 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.W88S (c.263G>C)

LegacyVariant: p.W88S (c.476G>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2220 https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88S (c.263G>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 36

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 36

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R177* (c.742A>T)

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 109

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 109

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown or unstated.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: R161* (c.694C>T)

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

GroupID/ KindredID: VHL 16

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

FamilyInfo: 4 affected members belong to this VHL type 2A family. One representative affected member was analyzed with this mutation, and VHL was diagnosed clinically in this index person. It is unclear as to whether the additional patients had this precise mutation, although assumed.

GroupPresentingHPOs: HP:0009711; HP:0002666; HP:0010797 (retinal capillary hemangioma, pheochromocytoma, hemangioblastoma)

GroupHPOFreeText: 3 individuals had Pheos, 3 had retinal capillary hemangiomas, but only 1 had a CNS hemangioblastoma.

GroupNotHPOs: HP:0005584; HP:0001737; HP:0009715 (renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients had the above tumors

GroupPreviousTesting: N/A

PreviouslyPublished: 11134110, 9681856, 11850829

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: 12

KindredID: 12

Case: M, 43Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

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: N/A

ClinVarID: 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?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: M, 46Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86S (c.256C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA020180 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.256C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: M, 60Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history.

CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

CasePresentingHPOs: HP:0006748, HP:0010797, HP:0005584, HP:0030405, HP:0009711, HP:0030393 (adrenal pheochromocytoma, hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumour, retinal capillary hemangioma, endolymphatic sac tumor)

CaseHPOFreeText: The patient had a right adrenal pheochromocytoma at age 35. The patient had two pheochromocytomas.

CaseNotHPOs: HP:0008221 (Adrenal hyperplasia)

CaseNotHPOFreeText: The patient did not have adrenomedullary hyperplasia.

CasePreviousTesting: N/A

PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

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: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: None (proband 10)

KindredID: 10

Case: M, 57Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s son was found with the same mutation, as well as RCC diagnosed at 30Y

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

CaseHPOFreeText: patient had hemangioblastoma diagnosed at 39Y, as well as retinal capillary hemangioma, renal cell carcinoma and pancreatic cysts diagnose at 57Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178R (c.533T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: III:7

KindredID: 7

Case: M, 13Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: 8 other members of this 3 generation family were observed to be affected with various presentations of VHL. This patient’s father and 3 cousins were confirmed with identical mutations. DNA samples were not available for all members in the family however.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: had hemangioblastoma at 13Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117G (c.349T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: None (proband 12)

KindredID: 12

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Only his mother was mentioned. She was also found with hemangioblastoma at 30Y, however she died before diagnosis; thus no DNA sample available.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: patient had hemangioblastoma of the CNS diagnosed at 31Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E94* (c.280G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 584477 https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E94* (c.280G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: age, sex, ethnicity unknown

DiseaseAssertion: Unknown

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Described as a positive control but not stated anything further

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied. This mutation was said to be a de novo, although no more inforation provided. However the asymptomatic father of patient was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198P (c.593T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223235 https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: II-2

KindredID: Family B

Case: F, 20Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Family positive pedigree showing patient’s father with RCC and CNS hemangioblastoma; as well as 2 siblings: brother and sister with CNS/spinal and retinal hemangioblastomas

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

CaseHPOFreeText: born with oculoauriculo-vertebral (Goldenhar) syndrome (has an asymmetrical face, coloboma at the right optic nerve with secondary amblyopia in her right eye, and a VA of hand motion). Her right eye was also treated for a peripheral retinal hemangioblastoma. She suffers from a small CNS hemangioblastoma. She has had surgery for multiple skin tags on the left side of her face, bilateral epibulbar lipodermoids and right eyelid coloboma

CaseNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79P (c.236G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351749311 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.236G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R79P (c.236G>C)

MultipleGeneVariants: N/A

PatientID: P12

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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: P11

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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: VHL 9

KindredID: VHL 9

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Two samples of VHL hemangioblastomas were represented here (.1, .2)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A - although likely duplicated in 24132471

SupplementalData: Yes - See Supplementary Table 1

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: Somatic, VHL, c.292C>A p.Tyr98*

PatientID: 31

GroupID/ KindredID: 31

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161G (c.481C>G)

LegacyVariant: p.R161G (c.694C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 618484 https://www.ncbi.nlm.nih.gov/clinvar/variation/618484/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R161G (c.481C>G)

MultipleGeneVariants: N/A

PatientID: 17

GroupID/ KindredID: 17

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111R (c.331A>C)

LegacyVariant: p.S111R (c.544A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751320 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.331A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S111R (c.331A>C)

MultipleGeneVariants: N/A

PatientID: 40

GroupID/ KindredID: 40

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L178P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 1

GroupID/ KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

CaseProblemVariantFreeText: 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)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 49

Case: F, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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: None

KindredID: 51

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

CaseProblemVariantFreeText: The protein change was written as Thr175 in the Supplemental but the nucleotide change corresponds to Tyr175.

LegacyVariant: N/A

ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL12

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had two benign pheochromocytomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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: The patient had LOH found in the BAC array CGH data.

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: V-37

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: V-24

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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

GroupID/ KindredID: F15

Case: Sex unknown, 32Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Noted of familial antecedents of phaeochromocytoma.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Unilateral pheo. Age of onset is 32Y0M.

CaseNotHPOs: HP:0006770; HP:0000107; HP:0006880; HP:0001737; HP:0009711 (clear cell renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175C (c.524A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36905 https://www.ncbi.nlm.nih.gov/clinvar/variation/36905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y175C (c.524A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F2

Case: Sex unknown, 26Y0M, Spanish

DiseaseAssertion: assumed VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: F66

Case: Sex unknown, 12Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found of pancreatic cysts

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: Multiple lesions on their retinal hemangioblastoma. Age of onset is 12Y0M.

CaseNotHPOs: HP:0006880; HP:0002666; HP:0000107; HP:0001737; HP:0006770 (cerebellar hemangioblastoma, pheochromocytoma, renal cysts, pancreatic cysts, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: F43

Case: Sex unknown, 27Y0M, 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: Development of Broad ligament cysts were also observed. Age of onset is 27Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 29

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.P86L (c.257C>T)

LegacyVariant: p.P157L (c.470C>T)

CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46 **

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: ** Patients 46, 50, 71, and 72 were reported previously in Aronoff et al, 2018 (PMID: 29437867) as family 5

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: CNS hemangioblamstoma

CaseNotHPOs: HP:0030421; HP:0009711; HP:0030405; HP:0006770; HP:0100634 (epididymal tumour, retinal capillary hemangioma, pancreatic endocrine tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm)

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

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

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

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PatientID: 32

KindredID: 32

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 1 - see here for more info)

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

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 61

KindredID: 61

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma; Epididymal neoplasm)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0006770 (Neuroendocrine neoplasm, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 7 - see here for more info)

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

Variant: p.R107G (c.319C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 28

KindredID: 28

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma, CCRC, and a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm)

CaseNotHPOs: HP:0030421; HP:0030405; HP:0009711 (epididymal tumour, pancreatic endocrine tumour, retinal capillary hemangioma)

CaseNotHPOFreeText: patient was not recorded to have retinal hemangioblastoma, an epididymal tumor, nor a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

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: 26

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and renal cell carcinoma.

CaseNotHPOs: HP:0001732 (Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692 (variants differ by one base pair; unclear which is accurate)

SupplementalData: N/A

Variant: p.D143Efs*13 (c.429_438del)

LegacyVariant: c.642del10bp

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131814, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131814

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: D143Efs*13 (c.429_438del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: CNS hemangioblastoma and renal cell carcinoma.

CaseNotHPOs: HP:0009711; HP:0001732 (Retinal capillary hemangioma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.C77Sfs*82 (c.230del)

LegacyVariant: c.443del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106239, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.230del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: C77Sfs*82 (c.230del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 105

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E173Rfs*29 (c.516del)

LegacyVariant: c.729del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645525089, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.516del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: E173Rfs*29 (c.516del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 25

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Retinal angioma, renal cell carcinoma and pancreatic cyst or tumor (unspecified).

CaseNotHPOs: HP:0010797 (Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.Q96_P97delinsH (c.288_290del)

LegacyVariant: c.501_503del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.288_290del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: Q96_P97delinsH (c.288_290del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 83

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Pancreatic cyst or tumor, CNS hemangioblastoma.

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.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: 362

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.395A>C germline variant of the VHL gene. Member 8813 had unknown renal involvement. Member 5862 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726 (Renal neoplasm)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Q132P (c.395A>C)

MultipleGeneVariants: N/A

PatientID: 6321

KindredID: 343

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: 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). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.R69Afs*63 (c.204dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.204dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: R69Afs*63 (c.204dup)

MultipleGeneVariants: N/A

GroupID: 509

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to have the c.500G>A germline variant of the VHL gene. Member 11209 presented with mild renal disease (RCC), member 10939 had unknown renal involvement and members 10901 and 10902 had no renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 512

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family presented with germline variants c.227T>A and c.228C>T occuring in cis in the VHL gene. Member 11876 presented with moderate renal disease (RCC) and member 13998 had unknown renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: 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.F76* (c.227_228delinsAA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320343, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_228delinsAA

gnomAD: N/A

VariantEvidence: Variants c.227T>A and c.228C>A occurred in cis, resulting in an amino acid change of p.Phe76Ter. This was mapped to c.227_228delinsAA.

MutationType: missense_variant;transversion; stop_gained

CivicName: F76* (c.227_228delinsAA)

MultipleGeneVariants: N/A

PatientID: II.1

KindredID: F1

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: N/A

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and kidney ischemic infarct at age 15 (DOB: 1991).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816685, https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition; splice_site_variant

CivicName: D143= (c.429C>T) and c.340+770T>C

MultipleGeneVariants: Germline, VHL, c.429C>T (p.Asp143Asp)

PatientID: CV2

KindredID: C

Case: M, 12Y0M, Serbian

DiseaseAssertion: Asymptomatic

FamilyInfo: Families were selected based on their clinical data and family history. Patient and his sister (CV1) are both currently asymptomatic, but possess the same variant as their father (CIV2), who was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. Patient’s grandfather, great grandfather and great uncle (CIII1; CII1, CII2) had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma. Out of the three of them, only the great grandfather had genetic testing performed and was found to have the same mutation as the patient. See pedigree in figure 1.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>A)

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577, https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 1

Case: F, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This woman (II-1) appears to have inherited this disease from her father, and passed it onto her 6 children, and many kin thereafter. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)

CaseHPOFreeText: Described as “probable” cerebellar hemangioblastoma and “probable” retinal angioma. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only assumed this member had the VHL mutation.

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: III-1

KindredID: 1

Case: M, Age Unknown (deceased), Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (III-1) appears to have inherited this disease from his mother and passed it onto his kin thereafter. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)

CaseHPOFreeText: Patient had cerebellar hemangioblastoma, along with retinal hemangiomas described as “probable”. No further details were provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: V32

DiseaseAssertion: VHL

GroupSize:2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Two family members had the same VHL gene mutation.

FamilyInfo: Positive.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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: V59

KindredID: V59

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:stop_gained

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

MultipleGeneVariants: N/A