ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.2930-1G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002440057 SCV002748565 likely pathogenic Cardiovascular phenotype 2022-09-16 criteria provided, single submitter clinical testing The c.2930-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 20 of the FLNC gene. 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. 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003102891 SCV003269684 pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2023-08-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 19 of the FLNC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy (PMID: 30067491; Invitae). ClinVar contains an entry for this variant (Variation ID: 1797807). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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