PatientID: 2

KindredID: 19

Case: F, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's son was the proband (1) and carried the mutation but was asymptomatic. The proband's uncle (7) carried the mutation and presented with symptoms. The proband's cousin (9) and first cousin once removed (22) were also found to have the mutation but were asymptomatic.

CohortInfo: 20 unrelated VHL families from an ethnically diverse cohort containing both affected and unaffected individuals.

CasePresentingHPOs:HP:0010797, HP:0005584, HP:0001732, HP:0000077 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, abnormality of the kidney)

CaseHPOFreeText: The patient presented with a hemangioblastoma at ages 17, 24, 30. At age 25 she presented with renal cell carcinoma and abnormalities of the kidney and pancreas.

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

CaseNotHPOFreeText: The patient did not have epididymal or ovarian cysts.

CasePreviousTesting: N/A

PreviouslyPublished: 31368132

SupplementalData: Supplementary file 1.

Variant: p.W88* (c.263G>A)

LegacyVariant: p.W88* (c.476G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 163

KindredID: 63

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 163) had a brother and niece who were both confirmed with the mutation. The brother (patient 164) had a CNS hemangioblastoma at 27, retinal angioma at 26, and pheochromocytoma at 8 years old. The niece (patient 165) was asymptomatic at the time of analysis. The proband also had a mother (patient 166) who had multiple pancreatic cysts/tumors and a pheochromocytoma at age 56, but for whom no DNA sample was available for analysis.

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

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

CaseNotHPOs: HP:0009711 (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.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/?new_evidence=true

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 88 (Second cousin)

KindredID: 18

Case: F, 52Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (18Y) and pheochromocytoma (17Y).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: I

KindredID: 12

Case: Sex Unknown, 21Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0001737 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 5Y. Presented with 5 retinal hemangioblastoma (5Y, 13Y, 14Y) 6 CNS hemangioblastoma (15Y, 17Y) 3 pancreatic cysts (15Y). Age at the end of study: 21Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-2 Deletion

MultipleGeneVariants: N/A