PatientID: 2

KindredID: 2

Case: M, 40Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A - family history was unremarkable. The paper states however that this patient inherited the duplication from a nonsymptomatic parent. Two siblings of patient 2, aged over 40 and also carriers of the same variant, underwent a thorough clinical evaluation, which was judged as negative.

CasePresentingHPOs: HP:0006880; HP:0011798 (cerebellar hemangioblastoma, renal oncocytoma)

CaseHPOFreeText: a 40-year-old male affected by cerebellar hemangioblastoma and renal oncocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21463266

SupplementalData: N/A

Variant: c.–65_–55dup11

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 517152 https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

CAID: N/A

gnomAD: 0.00009581 https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG

VariantEvidence: Quantitative Southern blot/real-time quantitative PCR analyses was normal in this patient. The 11 bp duplication is located within the promoter region of the VHL gene, in the vicinity of the main transcription initiation site, and within the binding site of several transcription factors. There is a possibility that the variant could alter transcription of the gene from the affected allele.

MutationType: 5_prime_UTR_variant

CivicName: c.–65_–55dup11

MultipleGeneVariants: N/A

PatientID: 221

KindredID: 221

Case: Sex Unknown, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Hemangioblastoma, Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17006605

SupplementalData: Table S1, S2 and S3

Variant: c.-61_-51dup

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 517152, https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

CAID: N/A

gnomAD: 0.00009581, https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG?dataset=gnomad_r2_1

VariantEvidence: Variant was reported as c.-65_-55dup11 which was mapped to c.-61_-51dup.

MutationType: splice_site_variant; duplication; plus_2_frameshift_variant; 5_prime_UTR_variant

CivicName: c.-61_-51dup11

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. Germline mutation c.-65_-55dup11 (mapped to c.-61_-51dup) was identified in prodand 221, 230 and 231. Proband 221 (12Y) presented with retinal capillary hemangioma. Proband 230 (40Y) presented with CNS hemangioblastoma. Proband 231 (9Y) presented with CNS hemangioblastoma. All three patients were previously published in PMID 17006605.