PatientID: II.1

KindredID: F6

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Splenomegaly

FamilyInfo: N/A

CasePresentingHPOs: HP:0001744 (Splenomegaly)

CaseHPOFreeText: Diagnosed with splenomegaly at age 6 months (DOB: 2014).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164H (c.492G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 456566, https://www.ncbi.nlm.nih.gov/clinvar/variation/456566/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transversion

CivicName: Q164H (c.492G>T) and c.340+574A>T

MultipleGeneVariants: Germline, VHL, c.340+574A>T

PatientID: I.1

KindredID: F10

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: This patient’s partner and two children were all carriers of the D143= (c.429C>T) germline VHL variant. Their son was diagnosed with splenomegaly and polycythemia and was homozygous for the variant. All other family members were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D143= (c.429C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 416990, https://www.ncbi.nlm.nih.gov/clinvar/variation/416990/

CAID: N/A

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/3-10188286-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition; synonymous_variant

CivicName: D143= (c.429C>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 10

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.F119L (c.357C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F119L (c.570C>G)

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 21

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.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: 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

PatientID: 218

KindredID: 81

Case: M, 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's sister (the proband) had the same germline mutation, and presented with a CNS hemangioblastoma at 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 20, and a pheochromocytoma at age 26.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, 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.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: 2

KindredID: 2

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's son also had this mutation, and presented with a CNS hemangioblastoma at age 22. The proband's mother presented with a CNS hemangioblastoma at age 61, and his brother presented with a CNS hemangioblastoma at age 33. His mother passed away before diagnosis, and there was no DNA sample available for his brother.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and pancreatic cysts at the age of 48.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, 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.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 200

KindredID: 77

Case: F, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 200) has six family members who passed away before diagnosis/ had no DNA sample available. Of the family who passed away before diagnosis: the proband's aunt 1 (patient 202) had a CNS hemangioblastoma at 27; the daughter of aunt 1 (patient 203) had a pheochromocytoma at 31; aunt 2 (patient 205) had a CNS hemangioblastoma at 43, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 48. Of the family for whom no DNA sample was available: the proband's mother (patient 201) had a CNS hemangioblastoma at 51, multiple pancreatic cysts/tumors at 46, and a pheochromocytoma at 25; the grandson of aunt 1 (patient 204) had a pheochromocytoma at age 9; and the son of aunt 2 (patient 206) had a pheochromocytoma at 16 and renal cell carcinoma + multiple pancreatic cysts/tumors at 21.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma and renal cell carcinoma at 36.

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 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: 27

KindredID: 9

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 27, presented at age 36 with a CNS hemangioblastoma, and renal cell carcinoma and multiple pancreatic cysts and tumors at 40.

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). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

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.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 3

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: No family information was provided for this patient. A total of 291 patients from 115 different families were included for analysis. VHL mutation confirmation was verified in at least one patient of each family.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 34. At age 37, they presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 98

KindredID: 33

Case: M, 43Y0M, 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:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband's 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.

CaseNotHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, 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.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: 187

KindredID: 72

Case: M, 67Y0M, 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:0005584; HP:0001732; HP:0001737 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 65, renal cell carcinoma at 54, and multiple pancreatic cysts/tumors at 67.

CaseNotHPOs: HP:0009711; HP:0002666 (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.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: 157

KindredID: 58

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

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: N/A

CaseHPOFreeText: The proband's nephew (son of sister) was asymptomatic at the time of analysis.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, 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.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: 224

KindredID: 83

Case: M, 53Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had the same germline mutation as his sister (the proband). His sister presented with a pheochromocytoma at age 38. His mother had a CNS hemangioblastoma at 52, but no genotyping information is available for her.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 53.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, 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.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: III-7

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father, the proband (II-4) carried the VHL mutation and presented with clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, and renal cysts. The patient's brother (III-6) carried the mutation but was asymptomatic. The patient's grandmother (I-2) died as a result of pancreatic cancer. His paternal aunt (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another paternal aunt (II-2) underwent surgery for breast cancer. See Figure 3 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Abdominal ultrasound examination of the patient revealed no abnormality.

CasePreviousTesting: 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: 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

PatientID: None

KindredID: 14482

Case: Age unknown, Sex unknown, Belgian

DiseaseAssertion: VHL

FamilyInfo: Paper states: Belgian family; Germline mutation

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 2178

KindredID: 113

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: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). 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.V87A (c.260T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750654, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.260T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V87A (c.260T>C)

MultipleGeneVariants: N/A

PatientID: 3404

KindredID: 209

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: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9829912

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

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

GroupID: 60

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 279.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID: 91

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 46YO, 19CA, 27F

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 Department of Uroglogy, Yokohama database, the Cambridge, Department of Pathology database, and the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family IDs 46YO, 19CA, 27F. 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.L118P (c.353T>C)

LegacyVariant: p.L118P (c.566T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428807 https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4783NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Two germline familial VHL mutations were associated with this family. They were: c.382C>T and c.381G>T and this data was taken from the National Cancer Institute database. It is unclear how many members belonging to Family ID 4783NCI had both mutations. 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.G127G (c.381G>T)

LegacyVariant: p.G127G (c.594G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421824 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.381G>T

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion; synonymous_variant

CivicName: G127G (c.381G>T)

MultipleGeneVariants: Germline, VHL, c.382C>T (p.Leu128Phe)

GroupID/ KindredID: 41F

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 41F. 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.Y156* (c.468T>G)

LegacyVariant: p.Y156* (c.681T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756053 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.468T>G

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: Y156* (c.468T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 41CA

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 41CA. 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.L153Cfs*6 (c.457delC)

LegacyVariant: FS (c.670delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421920 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.457delC

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: L153fs (c.457delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 49CA

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 49CA. 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.P154L (c.461C>T)

LegacyVariant: p.P154L (c.674C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 649525 https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 98CA

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 98CA. 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.Q96P (c.287A>C)

LegacyVariant: p.Q96P (c.500A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 625233 https://www.ncbi.nlm.nih.gov/clinvar/variation/625233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q96P (c.287A>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3759NCI, 3760NCI

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 IDs 3759NCI and 3760NCI. 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: 7728151

SupplementalData: N/A

Variant: p.Y112* (c.336C>A)

LegacyVariant: p.Y112* (c.549C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16602183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.336C>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: Y112* (c.336C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 147CA

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 147CA. 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.D121Mfs*38 (c.361delG)

LegacyVariant: FS (c.574delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421803 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361delG

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: D121fs (c.361delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 9YO, 51CE, 4327NCI, 160CA

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, the Munich, university of Freiburg and Institute of Pathology database, the National Cancer Institute database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 9YO, 51CE, 4327NCI, 160CA. 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.N78S (c.233A>G)

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

CaseProblemVariantFreeText: N/A

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

GroupID/ KindredID: 40CA

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 40CA. 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.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

PatientID: IV-28 [written in Table 2 as IV-24 - typo]

KindredID: 1

Case: F, 33Y0M, Iranian

DiseaseAssertion: assumed VHL

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient who proved to be symptomatic. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: HP:0011732; HP:0006880; HP:0010302 (abnormality of adrenal morphology, cerebellar hemangioblastoma, spinal cord tumor)

CaseHPOFreeText: Originally thought to be an asymptomatic carrier, however after follow-up was found to be symptomatic: brain MRI revealed multiple tutors, including a frontal mass (cerebellar tumor) with multiple spinal lesions, and an abdominal CT showed a 1.6x1.7 right adrenal mass. Additionally, this patient was pregnant at the time, to which was terminated at the 38th week of gestation with a caesarian section. She has two other children already.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

CasePreviousTesting: 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

PatientID: None

KindredID: 1

Case: Sex Unknown, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. Patient's mother did not undergo genetic testing but had a hemangioblastoma at age 50 and a pancreatic cyst or tumour at age 62. The patient's sister also had this mutation but was asymptomatic. Another one of the patient's sisters presented with hemangioblastoma (age 40), renal cell carcinoma (age 43), and pancreatic cysts or tumours (age 43). This patient died before diagnosis. The proband's brother also died before diagnosis and presented with hemangioblastoma and retinal angioma at age 27.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0009711 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with hemangioblastoma at age 35. At age 37 she presented with retinal angioma and pancreatic cysts or tumours. At age 39 she presented with renal cell carcinoma.

CaseNotHPOs: HP:0002666, HP:0009715 (pheochromocytoma, Papillary cystadenoma of the epididymis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

SupplementalData: N/A

Variant: p.Y98N (c.292T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750883 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y98N (c.292T>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: Unknown, 36Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

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

CaseHPOFreeText:The patient presented with hemangioblastoma at age 35. One year later he was found to have renal cell carcinoma and pancreatic cysts or tumors.

CaseNotHPOs: HP:0009711, HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA2499306941 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306941

gnomAD:N/A

VariantEvidence: N/A

MutationType: delins

CivicName:V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: Unknown, 24Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

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

CaseHPOFreeText:The patient presented with hemangioblastoma at age 18. At age 24 the patient had renal cell carcinoma and cysts/tumours of the pancreas.

CaseNotHPOs: HP:0009711, HP:0002666(retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117S(c.350G>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117S(c.350G>C)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: C

Case: Sex Unknown, 30Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: HP:0009713 (spinal hemangioblastoma)

CaseHPOFreeText: Patient had 2 spinal HBs. They however appeared absent of clinical manifestations of VHL disease prior to clinical and imaging scrutiny.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: A

Case: Sex Unknown, 35Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: two other symptomatic and one asymptomatic members of family A had this mutation. The symptomatic individuals had cerebellar hemangioblastomas, as well as spinal hemangioblastomas snd renal cysts.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Symptomatic before 29Y, clinically manifested as >3 cerebellar hemangioblastomas

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: 13

KindredID: C

Case: Sex Unknown, 17Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: asymptomatic

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient was asymptomatic at the time, likely due to young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: C

Case: Sex unknown, 30Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: assumed VHL

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0000107 (cerebellar hemangioblastoma, pancreatic cysts, renal cyst)

CaseHPOFreeText: Patient had 1 cerebellar HB, pancreatic and kidney cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PatientID: III-6

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma, Paraganglioma, Retinal capillary hemangioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient). Deceased.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: V-7

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666; HP:0002668 (Renal cell carcinoma, Pheochromocytoma, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: IV-12

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

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

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: Carrier 12 (sister to proband 7)

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Father, mother and sister (all relative to proband 7) had this variant. Both father and sister were asymptomatic. Proband and mother presented with unilateral PCC.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138Afs*6 (c.410dup)

LegacyVariant: 623insTTTGTtG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup

gnomAD: N/A

VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.

MutationType: insertion; plus_1_frameshift_variant

CivicName: P138fs (c.410dup)

MultipleGeneVariants: N/A

PatientID: Carrier 7 (niece to proband 3)

KindredID: 1

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

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: N/A

CaseHPOFreeText: N/A

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: Carrier 1 (sister to proband 1)

KindredID: 1

Case: F, 29Y0M, 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: 6

KindredID: 6

Case: F, 42Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial association - patient was selected from the group of familial VHL patients. This VHL germline mutation was detected in a close relative.

CasePresentingHPOs: HP:0001737; HP:0010797; HP:0030405 (pancreatic cysts; hemangioblastoma; pancreatic endocrine tumour)

CaseHPOFreeText: 2 single benign cysts, 6 macroscopic (and 1 microscopic) microcystic adenomas

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Val62Cysfs*5 (c.180delG)

LegacyVariant: p.V137Cfs*5 (c.393delG)

ClinVarID: 182986 https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V62fs (c.180delG)

MultipleGeneVariants: N/A

GroupID: 4577

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Each group represents a family.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: 2/3 members with pheochromocytoma, 1/3 members with CNS hemangioblastoma, 1/3 members with retinal angioma and 1/3 members with RCC. Diagnosed as a VHL Type 2B family.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

LegacyVariant: c.570C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 625240, https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 570, C to G (Phe to Leu), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.357C>G, p.Phe119Leu (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

KindredID: 1112

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030405; HP:0005584 (Pancreatic endocrine tumor, Renal cell carcinoma)

CaseNotHPOFreeText: The patient had no cysts (type or location was not specified).

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).

MutationType: stop_gained; missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 3Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother aged 38 was diagnosed with bilateral pheochromocytoma resected when she was the age of 18 years. She presented several relapses, the most recent one at the age of 32, when she was also diagnosed with cerebral angioma. Genetic testing revealed the presence of the VHL c 244 C>G (p. Arg 82 Gly) heterozygote mutation, while the tests for RET, SDHB, SDHC and SDHD were negative.

CasePresentingHPOs: HP:0001954; HP:0000980; HP:0001649; HP:0000822; HP:0002666; HP:0006748 (Recurrent fever, Pallor, Tachycardia, Hypertension, Pheochromocytoma, Adrenal pheochromocytoma)

CaseHPOFreeText: Several months history of febrile episodes, sweating and irritability. An abdominal ultrasound performed in a pediatric hospital revealed a right adrenal tumor mass. The clinical examination of our patient revealed: pallor, paroxysmal febrile episodes with irritability and sweating, tachycardia, hypertension. There was no palpable abdominal mass. Abdominal ultrasound showed a tumor of the right adrenal gland. MRI showed a right adrenal tumor confirmed by pathology to be a malignant pheochromocytoma. After 6 months from the complete resection of the tumor, the daughter is without any clinical symptoms, with normal blood pressure, normal ophthalmoscopy, no tumor markers and no evidence of tumor on cerebral or abdominal MRI.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82G (c.244C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1297059, https://www.ncbi.nlm.nih.gov/clinvar/variation/1297059/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

PatientID: III/3

KindredID: 2

Case: F, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Case II/3 (patient III/3's father) had retina angioma with renal carcinoma. Case II/2 (her uncle) also had the mutation and presented with renal carcinoma, central nervous system haemangioblastoma, pheochromacytoma and pancreatic cysts. Case I/1 (her grandfather) also had the mutation and presented with haemangioblastom. Pedigree: see Figure 2.

CasePresentingHPOs: N/A

CaseHPOFreeText: This patient has developed VHL disease as mentioned in the paper, however, specific clinical presentations of the disease are not outlined.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: R167W (8702C->T)

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

GroupID: 6B

DiseaseAssertion: assumed VHL

GroupSize: 9

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 33.8Y +/- 17.6Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 13 members total were described. it is unclear how many distinct families are reported in group 6B. 9 individuals were described. Phenotypic information was given for this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupHPOFreeText: 7 of the 9 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/9 had retinal angiomas at 25Y and 35Y, 1 had renal cell carcinoma (at 30Y), pancreatic cysts in 2 members (with an age of onset of 30 and 31Y), and 1 member with a genital system tumor (epididymis or broad ligament) at 24Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No patients were given with pheochromocytoma

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336; 28388566

SupplementalData: N/A

Variant: p.W88S (c.263G>C)

LegacyVariant: N/A

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

GroupID: 10

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 47.0Y +/- 18.4Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 6 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupHPOFreeText: 3 of the 6 members presented with CNS hemangioblastoma (mean age of 40.0Y), 3/6 had retinal capillary hemangiomas (at a mean age of 23Y), renal cell carcinoma in 3 members (at a mean age of 35.3Y), pancreatic cysts in 2 members (with age of onsets of 26 and 27Y), and 1 with a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament) (at age 18Y).

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: no members were found with pheochromocytomas

GroupPreviousTesting: N/A

PreviouslyPublished: 29330336

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 2 (group ID 5)

Case: F, 31Y0M, Chinese

DiseaseAssertion: asymptomatic

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 2, 4 members were described in a 3 generation family. The proband’s mother, uncle, and grandfather were also present with the VHL mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: N/A

CaseHPOFreeText: No characteristics were described

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 1

Case: M, 55Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0009713; HP:0006880; HP:0001901 (adrenal pheochromocytoma; paraganglioma; pancreatic endocrine tumor; spinal hemagnioblastoma, cerebellar hemagnioblastoma; polycythemia)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 7Y0M. He was found to have adrenal pheochromocytoma; paraganglioma, pancreatic endocrine tumor, spinal and cerebellar hemagnioblastoma, and polycythemia (see table 1). Patient was diagnosed with VHL subtype 2A at 54Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: III-10

KindredID: 1

Case: F, 27Y0M, 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’s mother, brother, and more, had the mutation. See Fig. 1 for full family pedigree.

CasePresentingHPOs: HP:0006748; HP:0005584 (adrenal pheochromocytoma; renal cell carcinoma)

CaseHPOFreeText: bilateral adrenal pheochromocytoma, right RCC

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: F54

Case: Sex unknown, 31Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006880; HP:0000107; HP:0001737 (cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Age of onset is 31Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: g.941_943delTCT

CaseProblemVariantFreeText: Patient was reported with the g. (genomic) coding positions. The g.941_943delTCT variant worked out to correspond with c.227_229delTCT.

ClinVarID: N/A

CAID: CA357012 http://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: II:3 (proband 4)

KindredID: 4

Case: M, 38Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s mother (I:1) was found with the same mutation and RCC at 63Y. The proband’s brother (II:1) died before diagnosis; thus no DNA sample available. He presented with hemangioblastoma at 19Y

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

CaseHPOFreeText: patient had hemangioblastoma at 22Y and retinal capillary hemangioma at 32Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90I (c.269A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: II:4 (proband 5’s sister 2)

KindredID: 5

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Her father and two sisters presented with this same mutation. The father had RCC diagnosed at 54Y. The one sister (II:3) had had pancreatic tumors at 36Y and hemangioblastomas at 38Y. The brother (II:1) appeared to be non-affected, while the other sister (II:2) had hemangioblastoma, renal cell carcinoma, pancreatic cysts, and Papillary cystadenoma of the epididymis diagnosed at 37Y; and pheochromocytoma at 39Y

CasePresentingHPOs: HP:0009711 (retinal capillary angiomas)

CaseHPOFreeText: had retinal angiomas at 34Y

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: 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: 22

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family. 

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

GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at the age of 15Y, 1 had cerebellar hemangioblastomas diagnosed at 20Y, and 1 member had RCC diagnosed at 38Y.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.H125Qfs*7 (c.374dupA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499307153 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307153

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: H125fs (c.374insA) 

MultipleGeneVariants: N/A

GroupID: 5

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 the mutation belonging to 1 family. This mutation (c.176delC) was found in 1 VHL family with 5 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 22Y, 4 patients had cerebellar hemangioblastomas diagnosed at a mean age of 24Y, and 2 patients had RCCs with a mean age of diagnosis of 60Y.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.P59Rfs*8 (c.176delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432536374 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.176delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P59fs (c.176delC)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 of the 573 patients discussed in this paper were found to the mutation belonging to 1 family. This mutation (c.194delC) was found in 1 VHL family with 7 patients.

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

GroupHPOFreeText: 3 patients had retinal angiomas diagnosed at a mean age of 18Y, 2 patients had cerebellar hemangioblastomas diagnosed at a mean age of 33Y, and 2 patients had RCCs with a mean age of diagnosis of 30Y and one single patient had pheos diagnosed at age 20Y.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.S65Wfs*2 (c.194delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432536395 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S65FS (c.194delC)

MultipleGeneVariants: N/A

GroupID: 85

Case: 27Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.538A>G) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCCs diagnosed at 27Y

CaseNotHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma; cerebellar hemangioblastoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.I180V (c.538A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 161401 https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/

CAID: N/A

gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10191545-A-G

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: The patient had three tumours, one hemangioblastoma of the central nervous system and two renal cell carcinomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

SupplementalData: N/A

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

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 3.3%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 2

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666, HP:0030405, HP:0011732 (pheochromocytoma, pancreatic endocrine tumour, Abnormality of adrenal morphology)

CaseHPOFreeText: The patient had three tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

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: The patient had a mosaic mutation with a mutated allele frequency of 5.7%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 20

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: Patient had VHL disease type 1; CNS-HB and RCC (see table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 2624160

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: 4

KindredID: 3

Case: M, 45Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL disease was described for this patient. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0000107; HP:0001737; HP:0000787 (cerebellar hemangioblastoma; spinal hemangioblastoma; renal cyst; pancreatic cysts; nephrolithiasis)

CaseHPOFreeText: At 40Y, Patient 4 was diagnosed with spinal and cerebellar hemangioblastomas, as well as multiple renal and pancreatic cysts. He was diagnosed with VHL disease type 1. At 43Y, renal cysts and stones were discovered. A year later, more spinal hemangioblastomas and renal stones were found. A year later, cerebellar lesions, as well as renal and pancreatic cysts were reported (see table 1).

CaseNotHPOs: HP:0002088; HP:0001392; HP:0005264; HP:0001743 (abnormal lung morphology; abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the lungs, liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.N90del (c.268_270del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524783, https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA645524783

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: N90del (c.268_270del)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 51Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: Patient 2 (the patient’s brother) presented with the same mutation and was diagnosed with VHL at age 45. The two brothers had very similar VHL clinical manifestations including cerebellar hemangioblastomas, renal cell carcinoma, and cysts in the pancreas. However, patient 1 had testicular and epididymal cysts, as well as lesions in the spine, which were absent in Patient 2. No other family history was noted. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0005584; HP:0009713; HP:0006880; HP:0000107; HP:0001737; HP:0030424; HP:0033608; HP:0000541; HP:0012215 (renal cell carcinoma; spinal hemangioblastoma; cerebellar hemangioblastoma; renal cyst; pancreatic cysts; epididymal cyst; pulmonary nodule; retinal detachment; testicular microlithiasis)

CaseHPOFreeText: At 44Y, Patient 1 exhibited cerebellar and spinal hemangioblastomas, as well as retinal detachment. He also had renal cell carcinoma in both kidneys and multiple cysts in one kidney, testis, and pancreas. He also reported a history of headaches and vertigo, leading to a diagnosis of VHL disease type 1. At 49Y, multiple nodules were found in his lungs and a year later, a nodule in the testis and scrotal lithiasis were detected. At 51Y, renal cell carcinoma was identified in the left kidney and his left epididymis was enlarged. Patient continued to present with left testicular and scrotal lithiasis, right retinal detachment, and multiple nodules in both lungs. However, tMutation:Germlinehe lung phenotype was asymptomatic (see table 1).

CaseNotHPOs: HP:0001392; HP:0005264; HP:0001743 (abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/Av

GroupID: 3315

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

GroupHPOFreeText: 1/4 members had a retinal angioma (hemangioma), 2 had CNS hemangioblastoma, and 2 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly previously published in PMID 9829911

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S182N (c.545G>A)

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

GroupID: 4325

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

GroupHPOFreeText: 1 of the 4 (1/4) patients were recorded with a hemangioblastoma; 3/4 with retinal angiomas

GroupNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC or pheos

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

PatientID: II-4

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0001732; HP:0002666 (retinal capillary hemangioma, abnormality of the pancreas, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: No VHL gene test was conducted but due to substantial family pedigree history, can assumed with confidence this mutation

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

GroupID/ KindredID: 14

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 5 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: 4 members had CNS hemangioblastomas, 1 had a retinal angiomas, 3 had RCC, 1 had a pancreatic abnormality

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: No family members appeared to have the above manifestation.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S111N (c.545G>A)

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 6

DiseaseAssertion: assumed VHL; asymptomatic

GroupSize: 22

GroupNumberMales: 14

GroupNumberFemales: 8

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 22 family members were recorded in this group with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See individual-case info by following GroupID/KindredID: 6

GroupPresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0001732; HP:0002666 (Renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, abnormality of the pancreas, pheochromocytoma)

GroupHPOFreeText: 12 family members had renal cell carcinoma, 10 had CNS hemangioblastomas, 5 had retinal hemangiomas, 7 had an abnormality of the pancreas (either cysts or a tumor), and 1 had a pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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

GroupID: 7

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.P71Lfs*61 (c.211_212insT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2501268513 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2501268513

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift

CivicName: P71fs (c.211insT)

MultipleGeneVariants: N/A

GroupID: 47

DiseaseAssertion: VHL

GroupSize: 15

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 15 patients are listed with this mutationt; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 5 patients were said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: N/A

GroupNotHPOFreeText: the other 10 members are said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: some are possibly published in PMID:15300849

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: 1

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.E46* (c.136G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351748085 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.136G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E46* (c.136G>T)

MultipleGeneVariants: N/A

PatientID: 13

KindredID: 354

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0030405 (pheochromocytoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (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: 7

KindredID: 503

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 503 was mentioned (Patient: 15). This patient was found to have a pancreatic endocrine tumour without pheochromocytoma or renal cell carcinoma.

CasePresentingHPOs: HP:0030405; HP:0002666; HP:0005584 (pancreatic endocrine tumour, pheochromocytoma, renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: 20

KindredID: 900

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P95Rfs*64 (c.284delC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030172 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030172

gnomAD: N/A

VariantEvidence:N/A

MutationType: minus_1_frameshift_variant

CivicName: P95Rfs*64 (c.284del)

MultipleGeneVariants: N/A

PatientID: CV1

KindredID: C

Case: M, 15Y0M, Serbian

DiseaseAssertion: Asymptomatic

FamilyInfo: Families were selected based on their clinical data and family history. Patient and his brother (CV2) 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

GroupID: None

KindredID: 17

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: 10 members of a South American family expressed this c.183C>G mutation.

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

GroupHPOFreeText: All 10 family members had a central nervous system hemangioblastoma. One also had a retinal angioma. Five had renal carcinoma. One patient per family with renal tumour <3 cm under follow up detected by imaging.

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: P61= (183C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 135951 https://www.ncbi.nlm.nih.gov/clinvar/variation/135951/

CAID: N/A

gnomAD: 0.0009632 https://gnomad.broadinstitute.org/variant/3-10183714-C-G

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL, Partial Deletion

GroupID: None

KindredID:9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed/Latino

GroupAgeRange: N/A

GroupInfo: Three members of a South American family expressed this c.344delA mutation.

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

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Pfs*44 (c.344delA)