PatientID: II.1

KindredID: 2

Case: M, 21Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Positive family history. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

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

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

VariantEvidence: N/A

MutationType: intron_variant

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

PatientID: II.2

KindredID: 3

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: The patient had an affected brother (II.1) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

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

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

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: N/A

MutationType: missense_variant;transition

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.340+770T>C

PatientID: II.1

KindredID: F1

Case: M, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: N/A

CasePresentingHPOs: HP:0001901 (Polycythemia)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition; splice_site_variant

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

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

PatientID: 1

KindredID: 1

Case: F, 16Y0M, Ukrainian

DiseaseAssertion: Assumed VHL

FamilyInfo: Her brother (patient 2) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901, HP:0005954, HP:0000077, HP:0001028 (polycythemia, pulmonary capillary hemangiomatosis, abnormality of the kidney, hemangioma )

CaseHPOFreeText: Patient had a hematocrit of 68%, erythropoietin level of 45 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo. She was diagnosed with polycythemia of unknown duration; at the age of 10 years, a pulmonary angioma was found and treated by a coil embolization. She continued to be polycythemic. At the age of 15 years, an abdominal computed tomography (CT) scan revealed a left renal mass, which on nephrectomy was determined to be a subcapsular hemangioma; there was no evidence of an angioma elsewhere. One year after surgery, she still remains polycythemic but has no evidence of a new or recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

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: None

KindredID: B

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: II.1

KindredID: F10

Case: M, 4Y6M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: This patient’s asymptomatic patients were both found to be carriers of the D143= (c.429C>T) germline variant in VHL. Their other child (II.2) also carried the gene. The current patient was the only one who was homozygous for the variant.

CasePresentingHPOs: HP:0001901; HP:0001744 (Polycythemia, Splenomegaly)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and splenomegaly at 4.5 years old (DOB: 2002).

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: Variant is present in allele 1 and 2 (i.e. homozygous).

MutationType: missense_variant;transition; synonymous_variant

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

MultipleGeneVariants: Germline, Beta Thalassemia

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: 2

KindredID: 1

Case: M, 10Y0M, Ukrainian

DiseaseAssertion: Asymptomatic

FamilyInfo: His sister (patient 1) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901 (polycythemia)

CaseHPOFreeText: Patient had a hematocrit of 63%, erythropoietin level of 271 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No tumor masses were detected by repeated CT scans of his abdomen or chest and by magnetic resonance imaging (MRI) of the head.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

MultipleGeneVariants: N/A