Submission Details

SCN5A 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 2/21/2025. 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.

SCN5A was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2005 (Olson et al., 2005, PMID: 15671429). Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. Numerous variants (missense, frameshift, nonsense) have been reported in humans with isolated DCM (Olson et al., 2005, PMID: 15671429; Ge et al., 2008, PMID: 19808398; McNair et al., 2011, PMID: 21596231; Morales et al., 2011, PMID: 20458009; Grosselin-Badaroudine et al., 2012, PMID: 22675453; Laurent et al., 2012, PMID: 22766342; Mann et al., 2012, PMID: 22999724; Zakrzewska-Koperska et al., 2018, PMID: 29871609; Calloe et al., 2018, PMID: 29506689; Gigli et al., 2019, PMID: 31514951; Doisne et al., 2020, PMID: 31930659). This gene-disease association is supported by mouse models, a human iPS cell culture model, and expression studies. SCN5A mRNA levels were markedly decreased in heart tissues obtained from DCM patients (Kepenek et al., 2019, PMID: 31520233). The myosin heavy chain-Snail transgenic mice displayed a DCM phenotype with conduction block and marked reduction of SCN5A expression (Hesse, et al., 2007, PMID: 17512504). Heterozygous and homozygous knock-in mouse models harboring SCN5A p.D1275N found in a patient with DCM displayed a DCM phenotype including intraventricular conduction block with marked reduction of cardiac sodium currents (Watanabe et al., 2011, PMID: 21824921). Furthermore, patient-derived human iPS cell-induced cardiomyocytes carrying SCN5A p.R219H showed reduced contraction, prolonged action potential duration, early afterdepolarization, and H+-leak currents (Moreau et al., 2018, PMID: 30218094). SCN5A has also been curated by the Long QT Syndrome gene curation expert group for familial long qt syndrome (Definitive, 09/25/2018), the Brugada Syndrome gene curation expert group for Brugada syndrome (Definitive, 11/21/2017), the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (Limited, 06/06/2019), the Catecholaminergic Polymorphic Ventricular Tachycardia gene curation expert group for CPVT (Disputed, 01/20/2021), the Short QT Syndrome gene curation expert group for short QT syndrome (Disputed, 10/27/2020), and the Congenital Heart Disease gene curation expert group for congenital heart disease (12/09/2024). In summary, SCN5A is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, 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 02/21/2025 and approved by the DCM GCEP on 05/30/2025.