Structural Evaluation of RYR2-CPVT Missense Variants and Continuous Bayesian Estimates of their Penetrance

BackgroundCatecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is strongly associated with rare missense variants in RYR2, the gene encoding the intracellular calcium release channel RyR2. Precision medicine is complicated by incomplete penetrance, particularly in the case of RYR2-CPVT variants ObjectiveTo improve structural understanding and clinical actionability of RYR2-CPVT incomplete penetrance. MethodsWe curated 179 manuscripts reviewed by three individuals to extrapolate RYR2-CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from RYR2 missense variants observed in gnomAD and ClinVar. We performed an RYR2-CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior on variant-specific features (in silico and structural) calibrated by heterozygote phenotypes. We compared the calibration of our Bayesian penetrance estimates and our previous described structural density metric with in silico predictors REVEL, AlphaMissense and ClinVar annotations, using Spearman rank-order correlations, and Brier Scores. Penetrance estimates were superimposed upon a cryo-EM structure of RyR2 to investigate hot-spot heterogeneity. ResultsFrom the literature and gnomAD, we identified 1,014 affected missense RYR2 heterozygotes (468 unique variants) among a total of 622,575 heterozygotes (5,181 unique variants). Among the predictors, our Bayesian prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared to ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all RYR2 missense variants are prospectively hosted at our Variant Browser website. ConclusionsBayesian penetrance scores outperform current tools in evaluating variant penetrance. We provide prospective CPVT penetrance values for 29,242 RYR2 missense variants at our online Variant Browser.