Submissions for variant NM_001458.5(FLNC):c.1210+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004625844	SCV005115294	likely pathogenic	Cardiovascular phenotype	2024-06-13	criteria provided, single submitter	clinical testing	The c.1210+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the FLNC gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed in at least one individual with a personal and/or family history that is consistent with dilated cardiomyopathy (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor 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. As such, this alteration is classified as likely pathogenic for FLNC-related dilated cardiomyopathy; however, its clinical significance for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005216283	SCV005857187	likely pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-02-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 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). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. 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.