ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.3193-2A>G

dbSNP: rs749889670
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695584 SCV000824093 likely pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2023-10-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 20 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 present in population databases (rs749889670, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 573818). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002442465 SCV002612169 uncertain significance Cardiovascular phenotype 2022-12-07 criteria provided, single submitter clinical testing The c.3193-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 21 in the FLNC gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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 altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002507212 SCV002815528 likely pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26 2021-08-20 criteria provided, single submitter clinical testing
GeneDx RCV003318627 SCV004022583 likely pathogenic not provided 2023-07-27 criteria provided, single submitter clinical testing Identified by exome sequencing in individuals participating in Geisingers MyCode Community Health Initiative and reported as likely pathogenic (Carruth et al., 2022); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27908349, 16199547, 35699965)

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