ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3975-1G>A

dbSNP: rs1060500370
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001386872 SCV001587263 pathogenic Neurofibromatosis, type 1 2022-12-13 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 30 (also known as 23.2) and introduces a premature termination codon (PMID: 10712197). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1073774). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 16944272, 25074460; Invitae). This sequence change affects an acceptor splice site in intron 29 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics RCV002377575 SCV002624566 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-04-26 criteria provided, single submitter clinical testing The c.3975-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 30 of the NF1 gene. This alteration was reported in an individual with a clinical diagnosis of neurofibromatosis type 1 (Pasmant E et al. Eur J Hum Genet. 2015 May;23:596-601). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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