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Dan Roden
Faculty Member
Last active: 3/24/2020

Protein structure aids predicting functional perturbation of missense variants in and .

Kroncke BM, Mendenhall J, Smith DK, Sanders CR, Capra JA, George AL, Blume JD, Meiler J, Roden DM
Comput Struct Biotechnol J. 2019 17: 206-214

PMID: 30828412 · PMCID: PMC6383132 · DOI:10.1016/j.csbj.2019.01.008

Rare variants in the cardiac potassium channel K7.1 () and sodium channel Na1.5 () 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 Na1.5 ( = 356) and K7.1 ( = 144) variants with in vitro characterized channel currents gathered from the literature. Here we investigated the ability to predict commonly reported Na1.5 and K7.1 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 Na1.5 peak current (adj. R = 0.27) and K7.1 + KCNE1 half-maximal voltage of activation (adj. R = 0.29). Additionally, use of structure-based functional density values improves loss-of-function classification of variants with an ROC-AUC of 0.78 compared with other predictive classifiers (AUC = 0.69; two-sided DeLong test  = .01). These results suggest structural data can inform predictions of the effect of uncharacterized and variants to provide a deeper understanding of their burden on carriers.

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