Structural Evaluation of <i>RYR2</i> -CPVT Missense Variants and Continuous Bayesian Estimates of Their Penetrance

Abstract

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

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