This resource was built and is maintained by the Kroncke lab at the Vanderbilt University Medical Center (Kroncke lab website). Please send any questions or comments to firstname.lastname@example.org.
SCN5A is a 2016 amino acid gene. It encodes NaV1.5, the main voltage-gated sodium channel in the heart. Coding-altering variants in SCN5A have been linked to many arrhythmia and cardiac conditions, including Brugada Syndrome Type 1 (BrS1 https://www.omim.org/entry/601144), Long QT Syndrome Type 3 (LQT3 https://www.omim.org/entry/603830), dilated cardiomyopathy (https://www.omim.org/entry/601154), cardiac conduction disease (https://www.omim.org/entry/113900), and Sick Sinus Syndrome (https://www.omim.org/entry/608567). Loss of function variants in SCN5A are associated with Brugada Syndrome and other cardiac conduction defects, and gain of function variants are associated with Long QT Syndrome. The risk of sudden cardiac death from these conditions can often be prevented with drug therapy or implantation of a defibrillator. SCN5A variants are often studied in vitro in heterologous expression systems using patch clamp electrophysiology. One challenge with SCN5A-related diseases is the issue of incomplete penetrance—only a fraction of variant carriers have disease phenotypes. Therefore, we believe that curating published patient data and in vitro functional data can contribute to a better understanding of each variant’s disease ris. We further suggest data such as function and structural location can inform an estimate of the risk of disease in the absence of heterozygote observations, a prior penetrance or positive predictive value for each variant. This analysis (described in greater detail on the Penetrance Analysis page) enables an estimate of penetrance for all variants for which these data are available, even before observing in a single individual.
The dataset described on this website is a dataset of patient data and in vitro patch clamp data. This dataset was first described in Kroncke and Glazer et al. 2018, Circulation: Genomic and Precision Medicine (https://pubmed.ncbi.nlm.nih.gov/29728395/). The data were curated from a comprehensive literature review from papers written about SCN5A (or Nav1.5, the protein product of SCN5A). We quantified the number of carriers presenting with and without disease for 1,712 reported SCN5A variants. For 356 variants, data were also available for five NaV1.5 electrophysiologic 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 associated with BrS1 (p < 0.001, rho = -0.44, Spearman’s rank test) and LQT3 disease penetrance (p < 0.001, rho = 0.37). Steady state V1/2 activation and recovery from inactivation also associated significantly with BrS1 and LQT3 penetrance, respectively.
This dataset was updated with papers published through January 2020. The description of the revised dataset published in Kroncke et al, 2020, PLOS Genetics. This paper also includes an updated Bayesian method for estimating the penetrance of each variant.
We have recently published an automated patch clamp study of >80 SCN5A variants (Glazer et al, American Journal of Human Genetics, 2020). This is a promising method for rapidly collecting in vitro functional data and reclassifying variants of uncertain significance. The full automated patch clamp dataset is available here [https://ars.els-cdn.com/content/image/1-s2.0-S0002929720301622-mmc2.csv] and has been integrated into the dataset on this website.
The functional parameters available in this website are peak current (overall function of the channel), V1/2 activation and inactivation (steady state voltages at which half of the channels open or inactivate, respectively), recovery from inactivation (characteristic time the channel takes to recover), and late/persistent current (current that persists after the channel "should" be closed). These functional parameters are all referenced to that of wild type by either percent (peak current, recovery from inactivation, or late current) or relative change (V1/2 activation/inactivation; mV).