Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378838 | SCV001576514 | likely pathogenic | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 30 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 (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 30975432; Invitae). ClinVar contains an entry for this variant (Variation ID: 1067540). 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 | RCV003365377 | SCV004054509 | likely pathogenic | Cardiovascular phenotype | 2023-08-16 | criteria provided, single submitter | clinical testing | The c.5199+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 30 of the FLNC gene. This variant co-occurred with variants in other cardiac-related genes in an individual with dilated cardiomyopathy (DCM) and sudden cardiac arrest (Asatryan B et al. Am J Cardiol, 2019 Jun;123:2031-2038). This variant has also been detected in an additional proband with DCM and sudden death (Smith E et al. J Am Heart Assoc, 2022 May;11:e024501). 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 donor site and may 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. Based on the supporting evidence, this variant is expected to be causative of FLNC-related dilated cardiomyopathy; however, its clinical significance for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is unclear. |