Protein structure aids predicting functional perturbation of missense variants in SCN5A and KCNQ1

Rare variants in the cardiac potassium channel K(V)7.1 (KCNQ1) and sodium channel Na(V)1.5 (SCN5A) are implicated in genetic disorders of heart rhythm, including congenital long QT and Brugada syndromes (LQTS, BrS), but also occur in reference populations. We previously reported two sets of Na(V)1.5 (n = 356) and K(V)7.1 (n = 144) variants with in vitro characterized channel currents gathered from the literature. Here we investigated the ability to predict commonly reported Na(V)1.5 and K(V)7.1 variant functional perturbations by leveraging diverse features including variant classifiers PROVEAN, PolyPhen-2, and SIFT; evolutionary rate and BLAST position specific scoring matrices (PSSM); and structure-based features including “functional densities” which is a measure of the density of pathogenic variants near the residue of interest. Structure-based functional densities were the most significant features for predicting Na(V)1.5 peak current (adj. R(2) = 0.27) and K(V)7.1 + KCNE1 half-maximal voltage of activation (adj. R(2) = 0.29). Additionally, use of structure-based functional density values improves loss-of-function classification of SCN5A variants with an ROC-AUC of 0.78 compared with other predictive classifiers (AUC = 0.69; two-sided DeLong test p = .01). These results suggest structural data can inform predictions of the effect of uncharacterized SCN5A and KCNQ1 variants to provide a deeper understanding of their burden on carriers.