ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3315-2A>G

dbSNP: rs1555614914
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002317246 SCV000670523 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2016-12-15 criteria provided, single submitter clinical testing The c.3315-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 26 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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 likely pathogenic.
Invitae RCV001039654 SCV001203193 pathogenic Neurofibromatosis, type 1 2024-01-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 25 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23913538; Invitae). ClinVar contains an entry for this variant (Variation ID: 484086). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 23913538). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV001039654 SCV002559950 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004553279 SCV004755976 likely pathogenic NF1-related disorder 2023-11-20 criteria provided, single submitter clinical testing The NF1 c.3315-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/484086/). Variants that disrupt the consensus splice acceptor site in NF1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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