PatientID: 3 (Father)

KindredID: 13

Case: M, 46Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 5 members of this family were found to harbour the deletion of one VHL allele. The proband (ID 1), sister (ID 2) and uncle (ID 5) were all asymptomatic. The grandmother (ID 9) presented with CNS hemangioblastoma (34Y).

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (34Y).

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

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: None

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0000957, HP:0000997, HP:0009737, HP:0006880, HP:0010797, HP:0200034, HP:0005306, HP:0001067 (Cafe-au-lait spot, Axillary freckling, Lisch nodules, cerebellar hemangioblastoma, hemangioblastoma, Papule, Capillary hemangioma, Neurofibromas)

CaseHPOFreeText: Referred to dermatology for multiple bleeding papules, the lesions of concern were exophytic, red, vascular papules located on the right jawline, front of the right shoulder, left lower aspect of the back, and right lower aspect of the back, consistent with lobular capillary hemangiomas. The patient was given the diagnosis of NF1 based on clinical findings that were first noted in childhood including multiple café au lait macules, axillary freckling, and Lisch nodules. VHL was suspected after magnetic resonance imaging showed hemangioblastoma of the left cerebellum during evaluation of sensorineural hearing loss. On the face, trunk, and extremities there were at least 20 scattered well-defined, ovoid, light-brown macules. Involving the chest, abdomen, and back were multiple discrete 4- to 8-mm subcutaneous rubbery-soft nodules. Axillary freckling was noted on both axilla and the groin.

CaseNotHPOs: N/A

CaseNotHPOFreeText: He did not have any additional tumors or cysts in the central nervous system or visceral organs that are common in VHL.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: sister

KindredID: C

Case: F, 34Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Family history is positive. Patient’s sister, and son all had the splice mutation, two with CNS hemangioblastomas and one with pheochromocytoma

CasePresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, papillary cystadenoma of the epididymis)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y, and adnexal papillary cystadenoma of probable mesonephric origin diagnosed at 35Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: proband

KindredID: D

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is said to be positive, however no other members were given. The patient’s son was asymptomatic and negative for the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145* (c.433C>T)

LegacyVariant: p.Q145* (c.646C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 625249 https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q145* (c.433C>T)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: Sex Unknown, 45Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had no family history of VHL disease.

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 at age 34, as well as renal cell carcinoma and abnormality of the pancreas at age 44.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115R (c.344A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70049376, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.344A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: H115R (c.344A>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006770, HP:0001732, HP:0010797 (clear cell renal cell carcinoma, abnormality of the pancreas, hemangioblastoma)

CaseHPOFreeText: The patient presented with a hemangioblastoma at age 34, clear cell renal cell carcinoma at age 37, and abnormality of the pancreas at age 37.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: M, 34Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None.

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:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19949673

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 3

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0009711; HP:0002666; (Retinal Capillary Hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: M,35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirteen patients with a supratentorial hemangioblastoma.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A