PatientID: 1

KindredID: 1

Case: F, 40Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880, HP:0006770, HP:0006748, HP:0001737, HP:0000107, HP:0009713 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Adrenal pheochromocytoma, Pancreatic cysts, Renal cyst, Spinal hemangioblastoma)

CaseHPOFreeText: The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the   kidney and  pancreas. Clinical symptoms and imaging features include Radicular lumbarpain, lowerlimb paresthesia &weakness/CT, MRI: contrastenhancing masses &erosion of lumbarspine & sacrum.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal kidney.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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) and I151N (c.452T>A)

MultipleGeneVariants: Germline, VHL, c. 452T>A (p.Ile151Asn)

PatientID: 1

KindredID: 1

Case: F, 40Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880, HP:0006770, HP:0006748, HP:0001737, HP:0000107, HP:0009713 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Adrenal pheochromocytoma, Pancreatic cysts, Renal cyst, Spinal hemangioblastoma)

CaseHPOFreeText: The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the   kidney and  pancreas. Clinical symptoms and imaging features include Radicular lumbarpain, lowerlimb paresthesia &weakness/CT, MRI: contrastenhancing masses &erosion of lumbarspine & sacrum.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal kidney.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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) and I151N (c.452T>A)

MultipleGeneVariants: Germline, VHL, c. 452T>A (p.Ile151Asn)

PatientID: 43

KindredID: 5959

Case: F, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Prp81Ser)

PatientID: 43

KindredID: 5959

Case: F, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Prp81Ser)

PatientID: II.1

KindredID: F4

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Variant c.340+694_340+711dup is inherited from mother (genetically confirmed) and variant R200W (c.598C>T) is assumed to be inherited from father.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901; HP:0002625; HP:0001342 (Polycythemia, Deep venous thrombosis, Cerebral hemorrhage)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia), deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232, https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: N/A

gnomAD: 0.0002016, https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition

CivicName: R200W (c.598C>T) and c.340+694_340+711dup

MultipleGeneVariants: Germline, VHL, c.340+694_340+711dup

MultipleGeneVariants: Germline, Factor V Leiden

PatientID: I.2

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

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

CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+617C>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+648T>C

PatientID: II.1

KindredID: F4

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Variant c.340+694_340+711dup is inherited from mother (genetically confirmed) and variant R200W (c.598C>T) is assumed to be inherited from father.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901; HP:0002625; HP:0001342 (Polycythemia, Deep venous thrombosis, Cerebral hemorrhage)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia), deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232, https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: N/A

gnomAD: 0.0002016, https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition

CivicName: R200W (c.598C>T) and c.340+694_340+711dup

MultipleGeneVariants: Germline, VHL, c.340+694_340+711dup

MultipleGeneVariants: Germline, Factor V Leiden

PatientID: I.2

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

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

CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+617C>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+648T>C