GroupID: None

KindredID:9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed/Latino

GroupAgeRange: N/A

GroupInfo: Three members of a South American family expressed this c.344delA mutation.

GroupPresentingHPOs: HP:0010797, HP:0009711, HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Pfs*44 (c.344delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70049370 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.344delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115Pfs*44(c.344delA) and P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL,c.c.183C>G (p.Pro61Pro)

Germline mutations were found in 20 Brazilian, VHL probands and their families. Peripheral blood samples were taken and genomic DNA was sequenced using PCR and Southern Blotting. The three exons of the VHL gene were amplified by PCR, sequenced in both strands with Big Dye terminators (Applied Biosystems), and collected and analysed on an ABI Prism 377 (Applied Biosystems). Germline rearrangements involving part or the entire VHL gene were detected by quantitative Southern blotting using g7 cDNA11 and a β globin probe. This mutation, H115Pfs*44 (c.344delA) , was found in a VHL type 1 family of 3 affected individuals (VHL family 9). This mutation caused a frameshift to occur leading to the protein terminating at residue 157. One had hemangioblastomas of the central nervous system, one with retinal angiomas, and one with renal carcinoma. Within this family a second mutation was also discovered in the VHL gene, P61= (183C>G), which was assumed to not be deleterious. ACMG codes as follows: A frameshift mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).

“None of the novel mutations were represented in 120 alleles from normal subjects in the Brazilian population suggesting that these base changes are not common polymorphisms.”