ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.4871C>T (p.Ser1624Leu)

gnomAD frequency: 0.00003  dbSNP: rs879255639
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001223109 SCV001395243 pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1624 of the FLNC protein (p.Ser1624Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with restrictive cardiomyopathy (PMID: 26666891, 30418145; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253126). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. Experimental studies have shown that this missense change affects FLNC function (PMID: 26666891). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004547624 SCV001443740 pathogenic FLNC-related disorder 2020-02-18 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in four patients from a family with restrictive cardiomyopathy (PMID: 26666891) and as a heterozygous change in a patient with hypertrophic cardiomyopathy (PMID: 30418145, 31245841). Functional studies have demonstrated that this variant results in protein aggregates consistent with disease in the histopathology of an affected patient's heart tissue and in transfected myoblast cell lines (PMID: 26666891). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0032% (1/31362) and thus is presumed to be rare. The c.4871C>T (p.Ser1624Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.4871C>T (p.Ser1624Leu) variant is classified as Likely Pathogenic.
DASA RCV002255096 SCV002526402 likely pathogenic Hypertrophic cardiomyopathy 26 2022-06-10 criteria provided, single submitter clinical testing The c.4871C>T;p.(Ser1624Leu) missense change has been observed in affected individual(s) (PMID: 26666891; 31245841; 32112656) - PS4_supporting.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26666891) - PS3_supporting. This variant is not present in population databases:rs879255639, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 26666891) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003150143 SCV003838410 likely pathogenic Cardiomyopathy 2021-10-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV003372670 SCV004095990 uncertain significance Cardiovascular phenotype 2023-09-08 criteria provided, single submitter clinical testing The p.S1624L variant (also known as c.4871C>T), located in coding exon 28 of the FLNC gene, results from a C to T substitution at nucleotide position 4871. The serine at codon 1624 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported to segregate with restrictive cardiomyopathy in one family (Brodehl A et al. Hum. Mutat., 2016 Mar;37:269-79). It was also identified in two siblings with hypertrophic cardiomyopathy (Ader F et al. Clin. Genet., 2019 10;96:317-329). This variant has been detected in a cardiomyopathy cohort; however, details were limited (Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). Based on internal structural analysis, this variant is predicted to be mildly disruptive (Amby internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM RCV000239540 SCV000297924 pathogenic Cardiomyopathy, familial restrictive, 5 2023-06-26 no assertion criteria provided literature only
OMIM RCV002255096 SCV003935305 pathogenic Hypertrophic cardiomyopathy 26 2023-06-26 no assertion criteria provided literature only

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