ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1186-2A>C

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002338043 SCV002635065 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2020-09-29 criteria provided, single submitter clinical testing The c.1186-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 11 in the NF1 gene. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. Other alterations impacting this same splice acceptor site have been identified in individuals with clinical diagnoses of neurofibromatosis type 1, however. Additionally, RNA data indicates three such variants (c.1186-2A>T, c.1186-2A>G, and c.1186-1G>C) result in the same abnormally spliced transcript as is predicted to result from c.1186-2A>C (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Brekelmans C et al. Hum. Mutat., 2019 10;40:1760-1767; Melloni G et al. Cancers (Basel), 2019 11;11:). The c.1186-2A>C variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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