PatientID: 5

KindredID: 3 (C)

Case: F, 38Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Family C consists of two parents and their two daughters. Patient's 14 year old daughter (see patient 4) shares the same mutation as him. She developed a retinal angioma at 12 years of age and a spinal cord hemangioma was detected at 14 years. The mother and the other daughter were free from any manifestations of the disease and showed no mutations in the VHL gene.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0006770 (spinal hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma)

CaseHPOFreeText: Radiological investigations detected bilateral kidney tumors, a cerebellar and a spinal cord hemangioma at 34 years of age. Histological analysis of the kidney verified RCC. Four years later (38 years of age), retinal angioma developed in both of his eyes.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: CA357042 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.340+1G>A

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: 34Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0006770; HP:0001737; HP:0000107; HP:0030393 (clear cell renal cell carcinoma; pancreatic cysts; renal cyst; endolymphatic sac tumor)

CaseHPOFreeText: Aged 34Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. ccRCC, pancreatic cysts, renal cysts, and endolymphatic sac tumors were all diagnosed at 34Y (See Table 1 & 2).

CaseNotHPOs: N/A

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: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: Sex Unknown, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive family history. The patient's mother had the same VHL mutation and presented with CNS hemangioblastoma.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

CaseHPOFreeText: The patient presented with clear cell renal cell carcinoma at age 34 and multiple pancreatic cysts or tumours at age 38.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030393, HP:0010797 (retinal capillary hemangioma, pheochromocytoma, endolymphatic sac tumor, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24986515

SupplementalData: N/A

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

LegacyVariant:N/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: II-26

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. His two daughters also appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0006770; HP:0009713; HP:0002031; HP:0003396; HP:0001649; HP:0001737; HP:0030424 (cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma, spinal hemangioblastoma, Abnormal esophagus morphology, Syringomyelia, Tachycardia, pancreatic cysts, epididymal cyst)

CaseHPOFreeText: CNS (including retinal angiomas) and renal involvement; with cerebellum hemangioblastoma found at age 34Y. An oesophageal abnormality that was treated with vagotomy at age 35Y. At age 44Y had bilateral clear cell renal cancer resulting in a right partial nephrectomy and left total nephrectomy. Same year had spinal surgery to treat a syrinx associated with a spinal cord haemangioblastoma, as well as cystic lesions in the pancreas (consistent with epididymal cystadenoma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

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