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

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is strongly associated with rare missense variants in RYR2, the gene encoding the intracellular calcium release channel RyR2.

We curated 179 articles reviewed by 3 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 (hereafter called Bayesian CPVT-prior) on variant-specific features (in silico and structural) calibrated by heterozygote phenotypes. We evaluated various features, including the Bayesian CPVT-prior, ClinVar, REVEL, and AlphaMissense against our observed CPVT penetrance, using Spearman rank-order correlations and Brier Scores. Penetrance estimates were superimposed on a cryo-EM structure of RyR2 to investigate hot-spot heterogeneity.

From the literature, we identified 1014 affected missense RYR2 heterozygotes (468 unique variants), and further supplemented by purpuroted unaffected heterozygotes in GnomAD to a total of 622 575 heterozygotes (5181 unique variants). Among the predictors, the Bayesian CPVT-prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared with 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 the Variant Browser website.

Traditional categorical variant annotations limit accurate disease risk assessment, especially in populations unascertained for disease. A probabilistic, population-calibrated penetrance framework enables more meaningful prospective variant interpretation. Our Bayesian CPVT-prior outperforms current tools in evaluating RYR2 variant penetrance. We provide prospective Bayesian CPVT penetrance values for 29 242 RYR2 missense variants at our online variant browser.