PatientID: 11

KindredID: 11

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: His son also had the mutation and had a CNS hemangioblastoma. The mother and sisters of patient 11 were also suspected to have VHL mutations, but their DNA was not evaluated.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0010797, HP:0000107, HP:0009711, HP:0005584,(hemangioblastoma, renal cyst, retinal capillary hemangioma, renal cell carcinoma)

CaseHPOFreeText: Patient 11 presented with nausea, vomiting, and left-side weakness, developed within 2 days. MR brain images revealed a hemangioblastoma-like cystic mass in the cerebellum (age 36) . He therefore underwent cerebellar tumor resection. When he was under observation, retinal hemangioma and renal cell carcinoma were detected at the ages of 41 and 48 years, respectively. He also had renal cysts at age 48.

CaseNotHPOs: HP:0001732, HP:0002666 (abnormality of the pancreas, pheochromocytoma)

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.500G>A)

MultipleGeneVariants: N/A

PatientID: 244

KindredID: 94

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 244) has a daughter with the variant (patient 245) who was asymptomatic at the time of assessment.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 28, renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 40, and retinal angioma at age 41.

CaseNotHPOs: N/A

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: 7

KindredID: 1

Case: Sex Unknown, 42Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs:; HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: 41Y at first ocular angioma (retinal capillary hemangioma).

CaseNotHPOs: HP:0010797; HP:0002666; HP:0005584 (hemangioblastoma, pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 13

Case: M, 44Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Son and brother presented with the same VHL variant. Son is asymptomatic. Brother presented with CNS hemangioblastoma at 29Y, retinal hemangioblastoma at 52Y, bilateral RCC at 43Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 43Y and bilateral renal cysts at 43Y. Nephew presented with CNS hemangioblastoma at 22Y, retinal hemangioblastoma at 18Y, bilateral RCC at 29Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 18Y but was not genetically confirmed.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

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

CaseHPOFreeText: CNS hemangioblastoma at 32Y, retinal hemangioblastoma at 44Y, bilateral RCC at 44Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 41Y. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0000107; HP:0002666 (Renal cyst, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: 290

KindredID: 114

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 38, and at age 41 presented with a retinal angioma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

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 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: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 21 (Aunt)

KindredID: 1

Case: F, 48Y0M, 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 1 (proband), 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).

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

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 39 and retinal angioma at age 41.

CaseNotHPOs: HP:0005584; HP:0001732; HP:0000077; HP:0010797 (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