PatientID: 3

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: renal cell carcinoma

FamilyInfo: None

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: deletion (deletion on chromosome 3 (>35kb, <90kb) resulting in complete loss of VHL gene)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: germline deletion on chromosome 3 (>35kb, <90kb) resulting in complete loss of VHL gene. Renal cell carcinoma sample from this patient shows a missense mutation R69C(c.205C>T) in the second copy of VHL gene.

MutationType: deletion

CivicName: Deletion AND R69C (c.205C>T)

MultipleGeneVariants: Somatic, VHL, c.205C>T (p.Arg69Cys)

PatientID: None

KindredID: 53

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001737 (hemangioblastoma, renal cyst, pancreatic cysts)

CaseHPOFreeText: 1 kidney and pancreatic cyst at first screening, as well as a hemangioblastoma at final screening (5 year follow up).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P(c.266T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: Sex Unknown, 59Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0002666 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233, https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179, https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S (c.241C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: Sex Unknown, 65Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0001737; HP:0002666 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 26

PatientID: I

Case: 37Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 26 consisted of 2 members; One other member (40Y) was diagnosed with a single spinal HAB, and a single cerebellar HAB at 38Y.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 32Y

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

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

GroupID/ KindredID: 22 / S 4

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This deletion was found in Family No. 22 with 1 member affected. Germline de novo mutations confirmed by analysis of parents’ DNA. Germline mutations (of deletion of exon 2-3) was not detected in DNA extracted from blood leucocytes of the parents.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exons 2, 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 2-3 DELETION

MultipleGeneVariants: N/A

GroupID/ KindredID: 13

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

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

GroupHPOFreeText: All 3 patients were tallied with a retinal capillary hemangiomas, 2 with cHemangioblastomas, and 1 with RCC. These phenotypes couldn’t be paired as it was not clear with each member.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149Pfs*10 (c.445delG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432421902 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.445delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: A149fs (c.445delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 17

Case: Age unknown, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: This mutation (R167Q (c.500G>A)) was found in Family No. 17 with 1 member affected.

CasePresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromcytoma)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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: 7

KindredID: 7

Case: Sex Unknown, 51Y0M, Ethnicity Unknown

DiseaseAssertion: clear cell renal cell carcinoma

FamilyInfo: N/A - not stated

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: Bilateral clear cell RCC was first diagnosed between 49-51Y of age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.340+578C>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 849869 https://www.ncbi.nlm.nih.gov/clinvar/variation/849869/

CAID: N/A

gnomAD: 0.0005097 https://gnomad.broadinstitute.org/variant/3-10184449-C-T

VariantEvidence: N/A

MutationType: splice_site_variant; intron_variant

CivicName: Splice Site (c.340+578C>T)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A - not stated

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: A pheochromocytoma (PCC) diagnosed first at 34Y was found, with follow up of a 10 year duration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.340+866C>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70046858 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B866C>A

gnomAD: N/A

VariantEvidence: Paper described this allele frequent as 0.02%, although not described in the gnomAD database.

MutationType: splice_site_variant; intron_variant

CivicName: Splice Site (c.340+866C>A)

MultipleGeneVariants: N/A

PatientID: S6150

KindredID: S6150

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 92 unrelated patients with VHL disease.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G104A(c.311G>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411966 https://www.ncbi.nlm.nih.gov/clinvar/variation/411966/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:G104A(c.311G>C)

MultipleGeneVariants: N/A

PatientID: V287

KindredID: V287

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N67_V74del (c.198_221del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524685, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.198_221del

gnomAD: N/A

VariantEvidence: Variant was reported as c.197del24 which was mapped to c.198_221del.

MutationType: inframe_deletion; deletion

CivicName: N67_V74del (c.198_221del)

MultipleGeneVariants: N/A

GroupID: V13

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 4/8 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: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 167827, https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: V73

KindredID: V73

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L140Qfs*3 (c.419_420del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223207, https://www.ncbi.nlm.nih.gov/clinvar/variation/223207/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as c.417_418del and mapped to c.419_420del.

MutationType: deletion; minus_2_frameshift_variant

CivicName: L140fs (c.419_420del)

MultipleGeneVariants: N/A

PatientID: V63

KindredID: V63

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: V12

DiseaseAssertion: V12

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity:N/A

GroupAgeRange: N/A

GroupInfo: This family had three members who all had the same VHL germline mutation.

FamilyInfo: Three members of this family had this germline mutation and were affected.

GroupPresentingHPOs:HP:0002666 (pheochromocytoma)

GroupHPOFreeText: This family was classified as VHL type 2B meaning they had a pheochromocytoma and presence of renal and pancreatic manifestations.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82P(c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 193118 https://www.ncbi.nlm.nih.gov/clinvar/variation/193118/

CAID:N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:R82P(c.245G>C)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 26

Case: F, 46Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for 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:0010797; HP:0005584; HP:0002666 (Hemangioblastoma, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastomas. Diagnosed with VHL Type 2B.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V87A (c.260T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: coding DNA and protein position (c.341T>C, p.Val114Arg) do not match reference sequence. “We found our error of changing the nucleotide code "A" to the three-letter code "Arg", which should be corrected to "ALA" based on the reference NM_001354723.1(VHL). It could be corrected as follows; NM_000551.3(VHL): c.260T>C (p.Val87Ala).” (Author Rhee comment)

ClinVarID: N/A

CAID: CA351750654, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351750654

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V87A (c.260T>C)

MultipleGeneVariants: N/A

PatientID: 33

KindredID: 33

Case: M, 33Y0M, 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:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastomas and renal cell carcinoma. 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 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L140Sfs*4 (c.417dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573051216, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA2573051216

gnomAD: N/A

VariantEvidence: Stated as c.417_418insT by the authors.

MutationType: duplication; plus_1_frameshift_variant

CivicName: L140Sfs*4 (c.417dup)

MultipleGeneVariants: N/A

PatientID: 53

KindredID: 53

Case: M, 36Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for VHL. No further details provided.

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

CaseHPOFreeText: CNS hemangioblastoma. 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 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: Exon 2-3 Deletion (c.341-?_642+?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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 44

KindredID: 44

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for VHL. No further details provided.

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:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral pheochromocytoma. CNS hemangioblastoma. Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346; “Kim, J. W., Choi, S. J., Kim, Y. K., Ahn, S. M., Song, K. E., Jung, S. H. et al. A case report of von Hippel–Lindau disease manifested in a monozygous twin. J. Korean Soc. Endocrinol. 20, 395–400 (2005)” (Reference 15 in current publication).

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: 5

KindredID: 5

Case: M, 43Y0M, 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:0010797; HP:0005562 (Hemangioblastoma, Multiple renal cysts)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastoma and renal cysts. Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817 and/or 19949673

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: 31

KindredID: 31

Case: F, 42Y0M, 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:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: CNS hemangioblastoma. 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 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1208816, https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 5

Case: F, 29Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL mutation - unknown relatives

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737 (hemangioblastoma; renal cell carcinoma; pancreatic cysts)

CaseHPOFreeText: With an age of diagnosis of VHL at 29

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patients with clinical manifestations suggestive of VHL or MEN2 were first screened for VHL or RET mutation, respectively. Possible screening of RET, SDHB and SDHD as well

PreviouslyPublished: N/A

SupplementalData: Yes

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

GroupID: None

Case: Sex Unknown, 71Y0M, Dutch

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0002666; HP:0000107 (Cerebellar hemangioblastoma, Pheochromocytoma, Renal cyst)

CaseHPOFreeText: This individual was classified as 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 31087189

SupplementalData: N/A

Variant: p.P154= (c.462A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621934, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.462A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; synonymous_variant

CivicName: P154= (c.462A>C)

MultipleGeneVariants: N/A

GroupID: None

Case: Sex Unknown, 42Y0M, Dutch

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0000107; HP:0001737 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 31087189

SupplementalData: N/A

Variant: p.V87Dfs*45 (c.259_260insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189242, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA913189242

gnomAD: N/A

VariantEvidence: N/A

MutationType: insertion; plus_1_frameshift_variant

CivicName: V87fs (c.259_260insA)

MultipleGeneVariants: N/A

PatientID: 18

KindredID: 355

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: NONE (unspecified large rearrangement)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: rearrangement_region

CivicName: rearrangement

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 63

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 63 was mentioned (Patient: 11). 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.Y175* (c.525C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 76

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NONE (unspecified large rearrangement)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: rearrangement_region

CivicName: rearrangement

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 40

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NONE (unspecified large rearrangement)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: rearrangement_region

CivicName: rearrangement

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: 151

KindredID: 55

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 150) has a father (patient 151) who was also confirmed with this germline mutation, and presented at 22 with a CNS hemangioblastoma and 28 with renal cell carcinoma. The proband presented with a CNS hemangioblastoma at 14 and multiple pancreatic cysts/tumors at 17. The proband also has a grandmother (patient 153) who presented with a CNS hemangioblastoma at 43, but who passed away before diagnosis/ genetic testing.

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

CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at 22 and renal cell carcinoma at 28.

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

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.I151S (c.452T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223215, https://www.ncbi.nlm.nih.gov/clinvar/variation/223215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: I151S (c.452T>G)

MultipleGeneVariants: N/A

PatientID: 43

KindredID: 15

Case: F , 21Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

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

CaseHPOFreeText: The proband's daughter (patient 43) presented with retinal angioma at 17, multiple pancreatic cysts/tumors at 18, pheochromocytoma at 19, and renal cell carcinoma at 21.

CaseNotHPOs: HP:0010797 (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.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 7

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 23, had a brother (patient 24) and father (patient 25) who were both genetically confirmed with the mutation. The brother presented with a CNS hemangioblastoma, renal cell carcinoma, and pancreatic cysts/tumors at age 32. The father presented with renal cell carcinoma and pancreatic cysts/tumors at age 58.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The proband, patient 23, presented with a CNS hemangioblastoma at age 31.

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

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.R69Afs*63 (c.204_205insG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.204_205insG

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: R69AFS*63 (c.204_205insG)

MultipleGeneVariants: N/A

PatientID: 59

KindredID: 22

Case: M, 14Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with multiple pancreatic cysts/tumors at 14 and pheochromocytoma at 11.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, 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.V87E (c.260T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750651; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.260T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V87E (c.260T>A)

MultipleGeneVariants: N/A

PatientID: 154

KindredID: 57

Case: M, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented at age 34 with retinal angioma, multiple pancreatic cysts/tumors, and renal cell carcinoma.

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

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.V155Dfs*17 (c.464_468del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2499306942; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306942

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V155fs (c.464_468delTGTAT)

MultipleGeneVariants: N/A

PatientID: 50

KindredID: 17

Case: F, 30Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with multiple pancreatic cysts/tumors and renal cell carcinoma at 30.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.L85P (c.254T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 376222; https://www.ncbi.nlm.nih.gov/clinvar/variation/376222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L85P (c.254T>C)

MultipleGeneVariants: N/A

PatientID: 131

KindredID: 49

Case: F, Age 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a pheochromocytoma at 18, retinal angioma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 31.

CaseNotHPOs: HP:0010797 (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.F136C (c.407T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065; https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 54

KindredID: 19

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 54) has a daughter who was genetically confirmed with the same mutation. The daughter was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 12, renal cell carcinoma and multiple pancreatic cysts/tumors at 33.

CaseNotHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, 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.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: 231

KindredID: 86

Case: M, 54Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 229) had a sister (patient 230) who was genetically confirmed with the mutation, and presented with a CNS hemangioblastoma at age 40. The proband's brother 1 (patient 231) was also confirmed with the mutation and had a retinal angioma at 25, and renal cell carcinoma at 54. The proband's brother 2 passed away before they could be diagnosed/ confirmed with the mutation, but they had a CNS hemangioblastoma at 35. Finally, the proband's nephew (son of brother 2) was genetically confirmed with the mutation and presented with renal cell carcinoma at age 30.

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

CaseHPOFreeText: The proband's brother (patient 231) had a retinal angioma at 25 and renal cell carcinoma at 54.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0001737; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625261, https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178R (c.533T>G)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 6

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's uncle's granddaughter (ie. the granddaughter of uncle 2), patient 19, was asymptomatic at the time of the study.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

PatientID: 123

KindredID: 43

Case: M, Age 60Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

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

CaseHPOFreeText: The proband's father (patient 123) presented with a CNS hemangioblastoma at age 27, renal cell carcinoma at age 48, and multiple pancreatic cysts/tumors at age 60.

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).

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

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/AcDNAposition:349

PatientID: 189

KindredID: 72

Case: F, 39Y0M, 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:0001737; HP:0001732 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 39, and multiple pancreatic cysts/tumors at 36.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, 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: 139

KindredID: 52

Case: F, 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:

CaseHPOFreeText: The proband's daughter was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0010797, HP:0001737; HP:0001732; HP:0005584; HP:0002666; HP:0009711 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, 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: 138

KindredID: 52

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

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

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

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).

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: 239

KindredID: 91

Case: M, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 239) has a sister (patient 240) who presented with multiple pancreatic cysts/tumors at 28.

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

CaseHPOFreeText: The proband presented with a retinal angioma at 14 and a CNS hemangioblastoma at 25.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0002666 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, 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: 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: N/A

PatientID: 25

KindredID: 7

Case: M, 58Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 23, had a brother (patient 24) and father (patient 25) who were both genetically confirmed with the mutation. The brother presented with a CNS hemangioblastoma, renal cell carcinoma, and pancreatic cysts/tumors at age 32. The father presented with renal cell carcinoma and pancreatic cysts/tumors at age 58.

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

CaseHPOFreeText: The proband's father, patient 25, presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, 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: p.R69Afs*63 (c.204_205insG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.204_205insG

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: R69AFS*63 (c.204_205insG)

MultipleGeneVariants: N/A

PatientID: 251

KindredID: 96

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 250) presented with a CNS hemangioblastoma at 23, retinal angioma at 17, and multiple pancreatic cysts/tumors at 19. His mother (patient 251) presented with a CNS hemangioblastoma at age 43, retinal angioma at 35, renal cell carcinoma/multiple pancreatic cysts/tumors at 44.

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

CaseHPOFreeText: The patient's mother presented with a CNS hemangioblastoma at age 43, retinal angioma at 35, renal cell carcinoma/multiple pancreatic cysts/tumors at 44.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: 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: N/A

PatientID: 53

KindredID: 18

Case: F, 11Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 51) has a father (patient 52) who passed away before he could be diagnosed/ genetically confirmed with this mutation. The father had renal cell carcinoma at 52. The proband's daughter (patient 53) was confirmed with the mutation and had retinal angioma at 11.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 31, and renal cell carcinoma and multiple pancreatic cysts/tumors at 32.

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797; HP:0002666 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma, 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.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

GroupID: None

DiseaseAssertion: VHL

GroupSize: 35

GroupNumberMales: 23

GroupNumberFemales: 12

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: 13 families (35 patients total, 33 of which are alive) in the partial deletion group had a CNS hemangioblastoma (see table 1)

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 32432044 (Potential overlap, same authors)

SupplementalData:  N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial Deletion)

MultipleGeneVariants: N/A

PatientID: II

KindredID: 19

Case: Sex Unknown, 1Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: 3 other family members presented with this VHL variant. Patients 19-I and 19-III were asymptomatic. Patient 19-IV presented with 2 retinal hemangioblastomas (10Y and 12Y) and kidney disease (17Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 0Y. Age at the end of study: 1Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Null (c.464-?_642+?del)

MultipleGeneVariants: N/A

PatientID: III

KindredID: 15

Case: Sex Unknown, 60Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 other family members presented with the same VHL variant. Patient 15-II presented with 2 pheochromocytoma (8Y) 2 CNS hb (12Y and 13Y) and 2 retinal hemangioblastomas (8Y, 12Y). Patient 15-I was asymptomatic.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Diagnosed with VHL at age 15Y. Presented with 2 pheochromocytoma (15Y). Age at the end of study: 60Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: I

KindredID: 13

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797, HP:0001737, HP:0009711 (hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseHPOFreeText: The patient was diagnosed with VHL at age 13. The patient had 8 retinal hemangioblastomas at ages 13, 16,17,18. The patient had 1 pancreatic cyst at age 17 and one CNS hemangioblastoma at age 17. The patient died at age 48.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

KindredID: 2

Case: Sex Unknown, 5Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: One other family member presented with his VHL mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 4Y. Age at the end of study: 5Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130I (c.388G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753916, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.388G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V130I (c.388G>A)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 8

Case: Sex Unknown, 35Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Diagnosed with VHL at age 15Y. Presented with 6 CNS hemangioblastomas (15Y) and 2 retinal hemangioblastomas (15Y). Age at the end of study: 15Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: N/A

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: Germline, VHL, c.319C>T (p.R107C)

PatientID: III

KindredID: 9

Case: Sex Unknown, 24Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: Two other family members (9-I and 9-II) carried the same mutation but were asymptotic.

CasePresentingHPOs: HP:0010797, HP:0001737 (hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: The patient had two CNS hemangioblastomas and two pancreatic cysts at age 16. The patient was diagnosed with VHL at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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: 10

KindredID: 10

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: paraganglioma

FamilyInfo: No details on family information provided.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: Patient had mediastinum paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126N (c.376G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 141044, https://www.ncbi.nlm.nih.gov/clinvar/variation/141044/

CAID: N/A

gnomAD: 0.00001988, https://gnomad.broadinstitute.org/variant/3-10188233-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: D126N (c.376G>A)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 3

Case: Sex Unknown, 49Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0005584; HP:0010797; HP:0001737; HP:0009711 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, renal cell carcinoma, hemangioblastoma, pancreatic cyst, retinal capillary hemangioma)

CaseHPOFreeText: The patient developed PPGL at 33Y of age, and a PNET at 49Y. They were also recorded with all of the above manifestations

CaseNotHPOs: HP:0000107 (renal cyst)

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

PatientID: 14

KindredID: 7

Case: Sex Unknown, 29Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405 (paraganglioma, pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: The patient developed PPGL at 29Y of age, and a PNET at 29Y.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0010797; HP:0009711; HP:0000107 (renal cell carcinoma, pancreatic cyst, hemangioblastoma, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: 4

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Four other family members were found to have the same mutation (Patient 7,8,9,10).

CasePresentingHPOs: HP:0002668, HP:0002666, HP:0030405, HP:0010797 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient was diagnosed with pancreatic endocrine tumor at age 44 and diagnosed with pheochromocytoma and paraganglioma at age 18.

CaseNotHPOs: HP:0009711, HP:0001737, HP:0000107, HP:0005584 (retinal capillary hemangioma, pancreatic cysts, renal cyst, 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: 13

KindredID: 6

Case: M, 22Y11M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 6, patient 12 was reported as having PPGL and PNETs at 36Y, along with renal and pancreatic cysts, and retinal HB. Their relation is not clear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient developed PPGL at 16Y of age. It was a right side Pheo measuring 1.7cm with no recurrence at follow up 83 Months after.

CaseNotHPOs: HP:0030405; HP:0010797; HP:0005584; HP:0001737; HP:0009711; HP:0000107 (pancreatic endocrine tumor, hemangioblastoma, renal cell carcinoma, pancreatic cyst, retinal capillary hemangioma, renal cyst)

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

PatientID: VHL-12

KindredID: 12

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Family history of VHL. No further details provided.

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

CaseHPOFreeText: Multiple CNS hemangioblastomas. Clinical classification: A1.

CaseNotHPOs: HP:0002666; HP:0001732 (Pheochromocytoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I109Tfs*50 (c.326del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658820709, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.326del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: I109TfsX50 (c.326del)

MultipleGeneVariants: N/A

PatientID: VHL-1

KindredID: 1

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

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.

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.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: VHL-17

KindredID: 17

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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:0002666; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma and multiple pheochromocytomas. Clinical classification: A2.

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

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: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: VHL-15

KindredID: 15

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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:0001732 (Hemangioblastoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma. Clinical classification: A2.

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

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: N/A (Case 3)

KindredID: 1

Case: Sex Unknown, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s two younger 9Y0M twin siblings possessed the same VHL variant and had abnormal vestibular assessments.

CasePresentingHPOs: HP:0001756 (Vestibular hypofunction)

CaseHPOFreeText: Following a genetic VHL diagnosis, patient presented with no audiovestibular symptoms. Vestibular assessment highlighted covert saccades in the left posterior semicircular canal on vHIT. Patient also showed signidicant assymmetry with weakness on the right side.

CaseNotHPOs: HP:0009713; HP:0006880 (spinal hemangioblastoma; cerebellar hemangioblastoma)

CaseNotHPOFreeText: peripheral hearing assessment and screening MRI of brain/spine were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1-3 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

PatientID: None (Twin)

KindredID: A-V6

Case: Sex Unknown, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals (twin brothers) in this family.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma. Died of VHL.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

SupplementalData: N/A

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Family and medical history make it likely that this patient had the p.R167W (c.499C>T) germline variant of VHL (as did this patient's twin brother) but this was not genetically confirmed. The variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected to c.499C>T.

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had no family history of VHL disease. Although, patient’s daughter possesses the same mutation.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0002666 (retinal capillary hemangioma; renal cell carcinoma; abnormality of the pancreas; pheochromocytoma)

CaseHPOFreeText: The patient presented with retinal capillary hemangioma at age 12, as well as renal cell carcinoma, abnormality of the pancreas, and pheochromocytoma at age 33.

CaseNotHPOs: HP:0030424, HP:0030393, HP:0010797 (epididymal cyst, endolymphatic sac tumor, hemangioblastoma)

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: N/A

KindredID: 13

Case: F, 32Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had family history of VHL disease. The patient's sibling presented with a hemangioblastoma, renal cell carcinoma and multiple pancreatic cysts or tumors at age 23 and then retinal hemangioma at age 24. He/she possessed the same mutation as the patient. The patient's mother presented with hemangioblastoma at age 43; but died prior to diagnosis and genetic testing.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

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

CaseNotHPOs: HP:0002666, HP:0030393, HP:0030424; HP:0009711 (pheochromocytoma, endolymphatic sac tumor, epididymal cyst, retinal capillary hemangioma; )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID:II-2

KindredID: 2

Case: F, Sex Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: The mother of the patient (I-2) was deceased, and the cause was unknown. The mother exhibited a brain tumor and coronary heart disease whilst alive. Multiple nodules were detected in the thyroid gland of the patient's eldest sister (II-1), but were not treated. The patient's brother (II-3) also had the mutation but was asymptomatic. See Figure 2 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: MRI of the brain of the patient's brother (II-3) indicated a nodule in the left cerebellar tonsil with a size of ~9.0×10.5 mm, which indicated the presence of a hemangioblastoma, astrocytoma or ependymoma. However, the diagnosis could not be confirmed.

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

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: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330, https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988, https://gnomad.broadinstitute.org/variant/3-10183605-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: IV-18

KindredID: 1

Case: F, 17Y0M, 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. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

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

CaseHPOFreeText: Patient had a bilateral PCC and retinal HB at 14Y which was surgically removed at the time. Histopathology was benign, and there was no case of relapse or metastatic dissemination.

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: IV-23

KindredID: 1

Case: M, 35Y0M, 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. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had a bilateral PCC at 31Y which was surgically removed at the time. He presently has no abnormal findings.

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: 1 (Proband)

KindredID: 13

Case: F, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 5 members of this family were found to harbour the deletion of one VHL allele. The sister (ID 2) and uncle (ID 5) were all asymptomatic. The father (ID 3) presented with CNS hemangioblastoma (34Y). The Grandmother (ID 9) presented with CNS hemangioblastoma (57Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Reported as “del one vHL allele”.

MutationType: deletion

CivicName: Null (del one VHL allele)

MultipleGeneVariants: N/A

PatientID: 10 (Uncle)

KindredID: 7

Case: M, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family were found to harbor the c.319C>G germline variant of the VHL gene. ID 11 presented with renal and pancreatic abnormalities, pheochromocytoma and other undefined phenotypes. ID 1 presented with pheochromocytoma. ID 2 presented with pancreatic abnormalities. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62. ID 4 presented with pheochromocytoma.

CasePresentingHPOs: HP:0002666; HP:0001732; HP:0010797 (Pheochromocytoma, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The patient presented with CNS hemangioblastoma (31Y, 35Y), pancreatic abnormalities (31Y) and pheochromocytoma (13Y).

CaseNotHPOs: HP:0009711; HP:0005584; HP:0000077 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 1

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 28, 2, 6, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified). ID 21 presented with retinal angioma and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a Pheochromocytoma at age 11.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 22 (First cousin once removed)

KindredID: 17

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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 1, 25 and 8 were asymptomatic. 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: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (36Y).

CaseNotHPOs: HP:0005584; HP:0002666; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, 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

PatientID: 2

KindredID: 1

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s 51Y0M mother also carried the same VHL mutation and had relapsing-remitting multiple sclerosis (MS) in the background of VHL disease. She was diagnosed with hemangioblastomas in the spinal cord and cerebellum, renal cell carcinoma, pancreatic neoplasm and a left ovarian dermoid cyst. She also exhibited vision loss in 1993 and then developed left lower extremity muscle weak in 2007. The limb weakness worsened in 2012 and decreased vision for 2 months, which raised a diagnosis of MS. Since then, treatment with corticosteroids showed partial response of symptoms and Copaxone was then initiated for treating MS. Their family history was significant for multiple cancers in prior generations. Her three sons were also affected by VHL disease, but no mention of genetic testing in these individuals. (see Fig.2 for Pedigree).

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0002666; HP:0030405; HP:0005584; HP:0000572 (Cerebellar Hemangioblastoma; Retinal capilllary Hemangioma; Pheochromocytoma; Pancreatic neuroendocrine tumor; Renal Cell Carcinoma, vision loss)

CaseHPOFreeText: Patient daughter also carried the same VHL mutation and had relapsing-remitting multiple sclerosis (MS) in the background of VHL disease. She had retinal and cerebellar hemangioblastomas, pheochromocytoma, pancreatic neuroendocrine tumor, and recurrent renal cell carcinoma. She exhibited numbness in her limbs and developed vision loss.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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: 6

KindredID: A (III-13)

Case: F, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (II:7) carried the VHL mutation and presented with hemangioblastoma, renal cell carcinoma, pheochromocytoma, and renal cysts. The patient had two brothers who both carried the mutation, one (III:12) presented with renal cell carcinoma, the other (III:11) with hemangioblastoma, renal cell carcinoma, renal cyst, and retinal capillary hemangioma. The patient also had one asymptomatic sister (III:10) who did not undergo genetic testing. On the mother's side of the family there was extensive history of VHL disease. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

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

CaseHPOFreeText: Diagnosed with hemangioblastoma at age 20. At 24, she was diagnosed with renal cell carcinoma. She underwent nephron-sparing surgery of the left side and one RCC measuring 2 cm in diameter was removed.

CaseNotHPOs: HP:0002666, HP:0000107 (pheochromocytoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: C

Case: Sex Unknown, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

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

CaseHPOFreeText: The patient had a hemangioblastoma diagnosed at age 29. The patient was diagnosed with renal cell carcinoma at age 31. A nephron-sparing surgery was performed on the left side. He was found to have one lesion with a diameter of 2 cm.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1-2 loss (c.1-?_463+?del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-2 Deletion

MultipleGeneVariants: N/A

GroupID: 35b

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: N/A

CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual did NOT have retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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: 0.000003976 https//gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID: 23

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.P86A (c.256C>G)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 93327 https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86A (c.256C>G)

MultipleGeneVariants: N/A

GroupID: 2b

DiseaseAssertion: VHL

GroupSize: 5

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: N/A

GroupHPOFreeText: These 5/15 patients with a VHL gene deletion did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: VHL gene deletion

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete Deletion)

MultipleGeneVariants: N/A

GroupID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: N/A

CaseHPOFreeText: This individual patient did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136LFS*23 (c.408del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

CohortInfo: The National Cancer Institute has a frozen tumour bank of ccRCC tumours that have been removed from VHL patients. We selected six patients, three males and three females, with at least five tumours from a single surgery from one kidney.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: One of the samples from this patient had few variants and clustered with the normal samples. Further inspection showed these samples were cyst-like rather than tumours, so they were excluded from further analysis. This suggests that the patient had renal cysts alongside ccRCC at age 45.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R176fsGfs*26 (c.526del)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName:R176fs (c.526del)

MultipleGeneVariants: N/A