A Rare Loss-of-Function SCN5A Variant is Associated With Lidocaine-induced Ventricular Fibrillation

The human genome contains over 4 million variant sites, as compared to the reference genome, including rare sequence variants, which have the potential to exert large phenotypic effects, such as susceptibility to drug toxicity. We report identification and functional characterization of a rare non-synonymous (p.A1427S) variant in the SCN5A gene that was associated with incessant and lethal ventricular tachycardia and fibrillation after administration of lidocaine to a patient with acute myocardial infarction. The variant, located in a highly conserved domain distinct from the predicted lidocaine binding site, decreased peak current density of the sodium channel. With the increasing availability of the whole exome and whole genome sequencing data, it would be possible to identify and characterize rare variants in SCN5A that might predispose to lethal ventricular arrhythmias.