ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3975-2A>T

dbSNP: rs864622431
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001237916 SCV001410703 pathogenic Neurofibromatosis, type 1 2022-03-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10712197, 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 963827). Disruption of this splice site has been observed in individual(s) with neurofibromatosis 1 (NF1) (PMID: 9003501, 10712197, 16944272). This variant is not present in population databases (gnomAD no frequency). 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 RCV002322138 SCV002626354 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2019-09-04 criteria provided, single submitter clinical testing The c.3975-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 30 in the NF1 gene. A different variant at the same location, c.3975-2A>G, has been reported in multiple individuals with neurofibromatosis type 1 and has been found to cause aberrant mRNA splicing (Upadhyaya M et al. Hum. Genet. 1997 Jan;99:88-92; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; Upadhyaya M et al. Hum. Mutat. 2006 Jul;27:716; Griffiths S et al. Fam. Cancer 2007;6:21-34; Pros E et al. Hum. Mutat. 2008 Sep;29:E173-93). In addition, 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. As such, this alteration is classified as a disease-causing mutation.

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