Submission Details

FLNC was originally evaluated for DCM by ClinGen DCM GCEP on October 9, 2020. Evidence of the association of this gene with DCM was re-evaluated on 4/09/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein.

FLNC was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2014 (Deo et al., 2014, PMID:(25633252). Deo et al. identified a splice site variant in one proband with DCM, but did not include details regarding genotype-phenotype correlation, family history, segregation data, or experimental evidence to support the pathogenicity of the variant, and therefore did not contribute to the genetic evidence score. However, since 2014, additional human genetic evidence supporting this gene-disease relationship has been reported and includes case-level data, segregation data, and case-control data. Numerous variants (missense, frameshift, truncating) have been reported in humans with isolated DCM (Ortiz-Genga et al., 2016, PMID: 27908349; Janin et al., 2017, PMID: 28436997; Sveinbjornsson et al., 2018, PMID: 30354339; others). In addition, this gene-disease assertion is supported by animal models. Begay et al. (2016, PMID: 28008423) generated a morpholino (MO) induced flnb knockdown in zebrafish. Zebrafish embryos injected with flncb MO showed more frequent cardiac phenotypes and reduced survival. The transgenic GFP-injected flncbþ p53 MO zebrafish embryos at 48 and 72 hpf demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. Nearly all of the injected embryos displayed varying degrees of reduced blood circulation, accompanied by an increase in retrograde blood flow and overall weaker contractility. Further, Fujita et al. (2012, PMID: 22020047) analyzed the effect of a nonsense FLNC variant found in medaka fish mutant "zacro". Mutants were characterized by an abnormally enlarged heart with a gradually reduced blood flow. At stage 28, prior to the heart looping, zac mutants showed blood congestion in the ventricle along with pericardial edema. Ruptures in the myocardium layer were detected in the zac mutants at stage 27, especially in the dorsal-right myocardium of the ventricle. As the endocardium was intact in zac mutants, the blood accumulation might have been caused by ineffective contraction of the torn myocardium. FLNC has also been curated by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel for myofibrillar myopathy (Definitive, 12/12/2017). In summary, FLNC is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 9, 2020 (SOP Version 7). This written summary was updated on 04/09/2025 and approved by the DCM GCEP on 05/30/2025.