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

BACKGROUND

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is strongly associated with rare missense variants in , the gene encoding the intracellular calcium release channel RyR2. Precision medicine is complicated by incomplete penetrance, particularly in the case of -CPVT variants.

OBJECTIVE

To improve structural understanding and clinical actionability of -CPVT incomplete penetrance.

METHODS

We curated 179 manuscripts reviewed by three individuals to extrapolate -CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from missense variants observed in gnomAD and ClinVar. We performed an -CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior on variant-specific features ( and structural) calibrated by heterozygote phenotypes. We compared the calibration of our Bayesian penetrance estimates and our previous described structural density metric with 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.

RESULTS

From the literature and gnomAD, we identified 1,014 affected missense 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 missense variants are prospectively hosted at our Variant Browser website.

CONCLUSIONS

Bayesian penetrance scores outperform current tools in evaluating variant penetrance. We provide prospective CPVT penetrance values for 29,242 missense variants at our online Variant Browser.