A Novel SCN5A Missense Variant Associated With Familial Non-Dilated Left Ventricular Cardiomyopathy

We report a novel SCN5A missense variant (c.655C>T (p.Arg219Cys)) in a family with non-dilated left ventricular cardiomyopathy, broadening the spectrum of SCN5A-related structural cardiac diseases. The proband, a 35-year-old man, presented with embolic stroke and myocardial fibrosis in the absence of ventricular dilation. He exhibited a significant arrhythmic burden, including premature ventricular complexes and a non-sustained ventricular tachycardia, prompting prophylactic subcutaneous defibrillator implantation. Genetic testing identified a heterozygous SCN5A variant, also present in five relatives with myocardial fibrosis of variable extent on cardiac magnetic resonance imaging. The variant affects a highly conserved residue within the voltage-sensing domain of the Nav1.5 channel and, according to ACMG criteria, is best classified as a variant of uncertain significance. Nevertheless, its segregation with disease and the established functional importance of this region of Nav1.5 suggest a possible role in the observed phenotype. This report highlights a structural cardiomyopathy phenotype potentially linked to SCN5A dysfunction and supports the growing recognition of overlap between ion channelopathies and cardiomyopathies.