Brett M Kroncke, Andrew M Glazer, Derek K Smith, Jeffrey D Blume, Dan M Roden

Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein NaV1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance. From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported SCN5A variants. For 356 variants, data were also available for 5 NaV1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation. We found that peak and late current significantly associate with Brugada syndrome (P<0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance (P<0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm. NaV1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of NaV1.5 variant electrophysiological abnormalities and help improve NaV1.5 variant classification.