PatientID: 9

KindredID: 9

Case: F, 16Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70K (c.208G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

CAID: N/A

gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: F, 41Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Daughter has the same mutation and presented with CNS hemangioblastoma.

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

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: https://doi.org/10.3803/jkes.2006.21.3.239

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: IV

KindredID: 3

Case: Sex Unknown, 21Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 3 other family members presented with his VHL mutation. Patient 3-I was asymptomatic. Patients 3-II and 3-III both presented with pheochromocytoma at 15Y.

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

CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with pheochromocytoma at 12Y and retinal hemangioblastoma at 10Y. Age at the end of study: 21Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 4

Case: Sex Unknown, 53Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 7Y. Presented with retinal hemangioblastoma at 7Y and 14Y. Age of death: 53Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

PatientID: None (XIII)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: asymptomatic

FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: M, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's uncle was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. The patient's mother and cousin also had the mutation but were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 2

Case: F, 29Y0M, African/African American

DiseaseAssertion: VHL

FamilyInfo: She was 23 weeks pregnant at the time of a pheochromocytoma resection. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother (although no testing conducted) and daughter were said to be investigated further and monitored long-term.

CasePresentingHPOs: HP:0006748; HP:0009713 (adrenal pheochromocytoma; spinal hemangioblastoma)

CaseHPOFreeText: At the time, the patient was 23 weeks pregnant and had bilateral adrenal phaeochromocytomas removed. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 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: 162

KindredID: 62

Case: F, 14Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient's mother presented with a CNS hemangioblastoma at age 28, and a renal cell carcinoma, multiple pancreatic cysts/tumors, and a pheochromocytoma at age 41.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 14.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0002666 (Retinal capillary hemangioma, Renal cell carcinoma, 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.R161* (c.481C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: 271

KindredID: 105

Case: F, 42Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented at age 48 with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0002666 (Retinal capillary hemangioma, Renal cell carcinoma, 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: Exon 2 Deletion (c.341-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

PatientID: 124

KindredID: 44

Case: M, Age 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 18, renal cell carcinoma and multiple pancreatic cysts/tumors at 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID: 24581539) and 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.W117S (c.350G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671; https://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: 194

KindredID: 74

Case: F, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 193, has a mother (patient 194) who was also found to have the same germline mutation. The proband had a CNS hemangioblastoma at age 16.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 36.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, CNS 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.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: 146

KindredID: 52

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

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

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister 2) was asymptomatic at the time of assessment.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

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

Variant: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 184

KindredID: 71

Case: M, Age 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother (patient 185) was confirmed with the mutation but was asymptomatic at the time of testing. The proband (patient 184) presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at 27, and multiple pancreatic cysts/tumors and a pheochromocytoma at age 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as 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: 265

KindredID: 104

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 265) has multiple family members who presented with VHL symptoms but were unconfirmed with the mutation, due to no DNA sample being available or due to death before diagnosis. The proband's son (patient 266) presented with a CNS hemangioblastoma at 19 and retinal angioma at 27. Their first brother (brother 1, patient 267) presented with a CNS hemangioblastoma at 36 and a retinal angioma at 46. Their nephew (son of brother 1, patient 267) presented with a retinal angioma at 16. Their second brother (brother 2, patient 268) had a CNS hemangioblastoma at 30, retinal angioma at 20, and renal cell carcinoma at 41. The proband's second nephew (son of brother 2, patient 269) had a retinal angioma at age 16.

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

CaseHPOFreeText: The proband presented at age 48 with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711; HP:0010797 (Retinal capillary hemangioma, 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: Exon 2 Deletion (c.341-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 8

Case: M, 66Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 26, presented with CNS hemangioblastoma at age 66, retinal angioma at age 66, renal cell carcinoma at age 37, and pancreatic cysts/ tumors at age 54.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336), and was likely previously published in Wang et al 2014 (24581539).

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 13

Case: F, Age Unknown, Indian

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had Unilateral PH (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 45Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

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.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient had VHL disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 28388566

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/A

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: None (Maternal Aunt)

KindredID: 1

Case: F, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Look to proband for more information on family history.

CasePresentingHPOs: HP:0006880; HP:0009711 (Cerebellar hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: Cerebellar/cerebral trunk hemangioblastoma. Multiple retinal hemangioblastomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25494863

SupplementalData: Figure 1

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD:

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: M, 18Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The family history revealed VHL in his mother, who died at the age of 40, and in his maternal aunt and grandmother, deceased at 30 and 33 years, respectively. His mother was operated on three times for cerebellar hemangioblastomas, the first at 13 years of age. She had also been treated for bilateral retinal hemangioblastomas since the age of 19. In addition, she had surgery for a renal tumor at the age of 32 and also had pancreatic cysts. She died of the diffuse hemangioblastomas in the posterior fossa. Variant is stated to be previously identified in the family but it is not clear which members have been genetically tested.

CasePresentingHPOs: HP:0006880; HP:0002893; HP:0007663; HP:0001510; HP:0000823; HP:0009711 (Cerebellar hemangioblastoma, Pituitary adenoma, Reduced visual acuity, Growth delay, Delayed puberty, Retinal capillary hemangioma)

CaseHPOFreeText: Referred at the age of 15 for decreased visual acuity of the right eye. Growth failure with short stature for age and lack of pubertal development was noted. This was confirmed by ophthal-mologic examination which also showed bitemporal quadranopsia. Two retinal vascular lesions had already been diagnosed and photocoagulated. Cerebral MRI examination visualized a voluminous pituitary adenoma (confirmed pathologically) with suprasellar extension compressing the optic fibres invading both cavernous sinuses. It also confirmed two small cerebellar hemangioblastomas. On follow-up, MRI showed a persistent pituitary adenoma (confirmed by pathology) with numerous mitoses. A cystic part of the main hemangioblastoma was also noted in the right cerebellum image.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: No renal lesion was found on ultrasound examination. Renal ultrasound examination was persistently normal.

CasePreviousTesting: N/A

PreviouslyPublished: 25494863

SupplementalData: Figure 1

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD:

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 14

Case: F, 11Y0M, Asian Indian

DiseaseAssertion: assumed VHL

FamilyInfo: None - Apparently sporadic

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

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic PGL

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: IV:10

KindredID: 1

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

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

CaseHPOFreeText: patient had cerebellar HB; renal cysts. Age of onset was 23Y, and surgery (operation) was 28Y

CaseNotHPOs: HP:0002666; HP:0030405; HP:0001737; HP:0002668 (pheochromocytoma, pancreatic endocrine tumor, pancreatic cysts, paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III:10

KindredID: 1

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: N/A

CaseHPOFreeText: unknown phenotype, however they were said to be affected

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: Death before genetic diagnostic, however presumed by authors due to extensive family history (See pedigree).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 23 / S 5

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This deletion was found in Family No. 23 with 1 member affected. No other family info was given

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 28

PatientID: II

Case: 24Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 17

Case: F, 3Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 6 members of this family tested positive for the c.496_506del germline variant of the VHL gene. ID 4 presented with CNS hemangioblastoma, retinal angioma and renal and pancreatic abnormalities. ID 25 and 8 were asymptomatic.ID 22 presented with CNS hemangioblastoma. ID 5 presented with retinal angioma. 2 members were assumed to have the variant but were not genetically confirmed (ID 20 and ID 11). ID 11 and 20 presented with CNS hemangioblastoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Abnormality of the kidney, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.V166Sfs*4 (c.496_506del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223229, https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

CAID: N/A

gnomAD: N/A

VariantEvidence: It is unclear from the publication if this variant is reported according to legacy (AF010238.1) or NM_000551.3 reference sequence. Clinical notes from the case confirm the reference sequence to be NM_000551.3.

MutationType: deletion; minus_2_frameshift_variant

CivicName: V166SFS*4 (c.496_506del)

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The four patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PatientID: VII-2

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:0009711 (Retinal capillary hemangioma)

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

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: VI-6

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (Asymptomatic)

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: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0002668 (Renal cell carcinoma, Retinal capillary hemangioma, 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: 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

PatientID: F119

KindredID: 1

Case: F, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a pheochromocytoma in the left adrenal gland. It was measured to be 3 cm in size and 23 grams in weight.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P(c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Aunt had a metastatic and progressinve pNET in the context of VHL.

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma, Pancreatic endocrine tumor)

CaseHPOFreeText: Underwent bilateral adrenalectomies for pheochromocytomas and a distal pancreatectomy and splenectomy for a grade 2 well-differentiated pNET. Post-operation, 3 new pNET’s developed and continued to grow. Due to the rate of growth of the lesion, her family history of malignant disease and concerns about her ability to manage resultant pancreatic endocrine insufficiency, she underwent a trial of primary somatostatin analog therapy. After 6 months, imaging showed significant decrease in size of all of the pNETs

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N?A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText:

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-

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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: Confocal staining shows the distribution of pVHL in the cell cytoplasm.

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: VHL-19

KindredID: 19

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

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

CaseHPOFreeText: Multiple hemangioblastoma of the CNS and spinal cord. Bilateral renal cell carcinoma.

CaseNotHPOs: HP:0001737, HP:0002666, HP:0009711 (pancreatic cysts, pheochromocytoma, retinal capillary hemangioma)

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: 19

KindredID: 19

Case: 43Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0030405; HP:0009711 (hemangioblastoma; renal cell carcinoma; pancreatic endocrine tumor; retinal capillary hemangioma)

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Stated in paper as “del VHL”; complete vhl gene deletion

MutationType: deletion (exon_loss_variant)

CivicName: DELETION

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: M,35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had a meckel cave hemangioblastoma at age 28. The patient had a papillary edema and pituitary stalk hemangioblastoma at age 34. The patient died of VHL disease.

CaseNotHPOs: N/A

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: N/A (case)

KindredID: 1

Case: F, 19Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Non-consanguineous parental relationship; second child; no mention of VHL in the family.

CasePresentingHPOs: HP:0010797; HP:0001713; HP:0002039; HP:0001824 (Hemangioblastoma; pancreatic cysts; anorexia; weight loss)

CaseHPOFreeText: Healthy from birth, this patient was referred to a psychiatric inpatient at 19Y with the weight loss and weakness, and the suspicion on anorexia nervosa. AN was not met according to the DSM-5 or ICD-10 (despite anorexic tendencies). There were also no tendencies towards an eating disorder. Patient developed progressive gait abnormality, along with bilateral dysmetria. MRI revealed a massive lesion with vascular characteristics suggestive of a HB in the fourth ventricle causing hypertensive hydrocephalus. Abdominal CT scan revealed cystic lesions throughout the parenchymatous portion of the pancreas, suspected to be related to VHLs. Together, supported the diagnosis of VHL. The patient underwent surgery of the brain, and radiotherapy which proved to work in small degrees.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: All blood tests, urinalysis and chest X‑ray were unremarkable. She also had no pheochromocytoma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 11Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

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

CaseHPOFreeText: Benign bilateral pheochromocytoma and retinal angioma at age 11

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.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: 52

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.H191Tfs*11 (c.571delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658795182 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.571delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H191FS (c.571delC)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s aunt presented with Hodgkin’s lymphoma at 38Y and was deceased at 40Y. The patient’s father presented with liver cancer at 72Y and was deceased at 74Y. Additionally, the patient’s deceased grandfather had an unspecified cancer. The patient’s son presented with unilateral pheochromocytoma at 13Y. The patient’s daughter presented with pheochromocytoma at 12Y, and bilateral retinal hemangioblastoma, right adrenal pheochromocytoma, and islet cell neuroendocrine carcinoma of the pancreas with nodal metastasis at 20Y, and was found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, retinal hemangioblastoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 12Y and retinal hemangioblastoma at 13Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.*214Lext*14(c.641G>T)

LegacyVariant: N/A

ClinVarID: 223236, http://www.ncbi.nlm.nih.gov/clinvar/variation/223236

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_loss

CivicName: *214Lext*14(c.641G>T)

MultipleGeneVariants: N/A

PatientID: V-14

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-23

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: F, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, Partial Deletion

GroupID: V43

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 4/7 members of this family that underwent genetic testing had the same mutation.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Diagnosed with VHL Type 1.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Likely 15300849

SupplementalData: N/A

Variant: p.L158dup (c.473_474insTTT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320246, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320246

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: L158dup (c.473_474insTTT)

MultipleGeneVariants: N/A

PatientID: N/A (proband's nephew)

KindredID: 2

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: The same point mutation of VHL (c. 232A>T; p.Asn78Tyr) was identified in three family members: 2 female and 1 male (one of which is his parent). His grandmother died of stroke at early of 50 years.

CasePresentingHPOs: unknown

CaseHPOFreeText: refused for further examinations for VHL-related lesions.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78Y (c.232A>T)

LegacyVariant: N/A

ClinVar: 223167 https://www.ncbi.nlm.nih.gov/clinvar/variation/223167/

CAID: CA357056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.232A%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78Y (c.232A>T)

MultipleGeneVariants: N/A

GroupID: 14a

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 2/3 patients with a Q164* (c.490C>T) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: A-V5

KindredID: A-V5

Case: F, 37Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma, Pancreatic endocrine tumor)

CaseHPOFreeText: Bilateral pheochromocytoma and pancreatic islet cell carcinoma. Diagnosed with VHL type 2.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

SupplementalData: N/A

Variant: p.A149T (c.445G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223213, https://www.ncbi.nlm.nih.gov/clinvar/variation/223213/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: A149T (c.445G>A)

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M (deceased), Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

GroupID: 19

DiseaseAssertion: assumed VHL

GroupSize: 24

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 47.8Y +/- 12.7Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 10 families with 24 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, pheochromocytoma)

GroupHPOFreeText: 15 of the 24 members presented with CNS hemangioblastoma (with a mean age of onset of 35.6Y), retinal capillary hemangioma in 4 members (at the mean age of 23.0Y), renal cell carcinoma in 10 members (at the mean age of 38.3Y), pancreatic cysts in 5 members (at the mean age of 37.2Y), and pheochromocytoma in 9 members (at the mean age of 36.3Y)

GroupNotHPOs: HP:0009715 (papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No members had a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament)

GroupPreviousTesting: N/A

PreviouslyPublished: 24581539 (family #11); 29330336 (as 7 families of 18 people); 28388566 (family #78, 79, 80, 81, 82, 83)

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: 6

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL. Parents underwent genetic testing and were not found to harbor the P102Rfs*57 (c.305del) germline variant of the VHL gene, confirming a de novo mutation in the current patient.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0002894 (Hemangioblastoma, Renal cell carcinoma, Neoplasm of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cystadenoma and Renal carcinoma.

CaseNotHPOs: HP:0009711; HP:0002894; HP:0002666 (Retinal capillary hemangioma, Neoplasm of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P102Rfs*57 (c.305del)

LegacyVariant: N/A

CaseProblemVariantFreeText:

ClinVarID: N/A

CAID: CA658820710, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.305del

gnomAD: N/A

VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: deletion; minus_1_frameshift_variant

CivicName: P102fs (c.305del)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A - Not specified

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: VHL syndromic HB

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96_P102del (c.287_307del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106190 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573106190

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: Q96_P102del (c.287_307del)

MultipleGeneVariants: N/A

PatientID: 31

KindredID: 22

Case: Sex Unknown, 32Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: stated as a familial VHL. 1 other family member (patient 30) with that same mutation was stated with an age of 56. This patient has RCC, renal cysts, pancreatic cysts, and CNS hemangioblastoma and retinal capillary hemangioblastomas.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584; HP:0000107 (hemangioblastoma, pancreatic cyst, renal cell carcinoma, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668, HP:0002666; HP:0009711; HP:0030405; (Paraganglioma, pheochromocytoma, retinal capillary hemangioma, pancreatic endocrine tumor)

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: None (father)

KindredID: 1

Case: M, 78Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 37Y old daughter had multiple cysts (RCC) in both kidneys and the same (c.349T>A) mutation

CasePresentingHPOs: HP:0000107; HP:0005584; HP:0006770 (renal cysts; renal cell carcinoma, clear cell renal cell carcinoma)

CaseHPOFreeText: VHL patient underwent left nephrectomy and right partial nephrectomy (subtotal nephrectomy). Histopathological examination revealed clear cell type renal cell carcinoma (RCC)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 51Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H191Tfs*11 (c.571delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658795182 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.571delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H191Tfs*11 (c.571delC)

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL10

Case: F, 65Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one malignant pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

Variant: p.Y156H (c.466T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756040, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.466T%3EC

gnomAD: N/A

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

MutationType: missense_variant;transition

CivicName: Y156H (c.466T>C)

MultipleGeneVariants: N/A

PatientID: I:1

KindredID: 4

Case: F, 63Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s one son (II:3) was found with the same mutation and hemangioblastoma at 22Y and retinal capillary hemangioma at 32Y. Her other son (II:1) died before diagnosis; thus no DNA sample available. He presented with hemangioblastoma at 19Y

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCC at 63Y

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: N/A (mother)

KindredID: 1

Case: F, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Prior to her daughter being tested, there was no family history of PCC/paraganglioma (PGL), multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) or VHL. Genetic testing and observation found the mutation (c.361G>C) in her daughter, who also presented with extraadrenal and adrenal pheochromocytoma.

CasePresentingHPOs: HP:0009713; HP:0006748; HP:0030405 (spinal hemangioblastoma, adrenal pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: MRI of the brain, spine and abdomen revealed multiple, asymptomatic VHL-associated lesions. These included a spinal haemangioblastoma, bilateral T2-hyperintense adrenal lesions (18 mm and 12 mm), subsequently confirmed to be PCCs, and two pancreatic lesions (11 mm and 16 mm), subsequently confirmed to be grade 1 neuroendocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: SDHA, SDHB

SupplementalData: N/A

Variant: p.D121H (c.361G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753752 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: D121H (c.361G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 28

PatientID: II

Case: 24Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M (deceased), Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: The proband was part of a cohort of apparently sporadic cases of pheochromocytoma/ paraganglioma, implying this individual had no family history of VHL disease or pheochromocytoma.

CasePresentingHPOs: HP:0006748 (Adrenal Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: ex. 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