Abstract
PurposeVariants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk. MethodsAmong 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. ResultsWe demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ −1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. ConclusionSTRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.
Highlights
Since variants in MYBPC3 present in gnomAD with allele frequencies of >4E-05 and absent in Sarcomeric Human Cardiomyopathy Registry (SHaRe) are unlikely to be independently pathogenic for hypertrophic cardiomyopathy (HCM), these variants were included in our list of benign MYBPC3 variants.[14]
We began by evaluating all MYBPC3 missense variants of uncertain significance (VUS) within SHaRe using STRUM
We have identified a subpopulation of patients with a MYBPC3 missense VUS that are predicted to disrupt subdomain protein folding (STRUM+) who exhibit clinical outcomes indistinguishable from patients with a pathogenic MYBPC3 variant
Summary
Genetic variant interpretation is an ongoing challenge in clinical medicine, when the gene of interest lacks robust functional assays.[1,2] A variety of computational algorithms have been developed to predict variant pathogenicity, but their sensitivity and specificity are often poor, when applied broadly across different diseases and different genes.[1,3] Loss-offunction (LoF) pathogenic variants are common,[1,4,5] resulting from either frameshift or nonsense variants creating a premature stop codon, splice errors, disruption of enzymatic activity, alteration of protein–protein interactions, or protein misfolding.[1,6,7] Recognizing a common mechanism by which variants in a particular gene lead to LoF can inform the development of gene-specific computational algorithms to more accurately predict pathogenicity among variants that cannot be confidently classified based on clinical and family data alone.[6,7] we focus on MYBPC3 (encoding the protein, cardiac myosin binding protein C, or MyBP-C). Pathogenic variants in MYBPC3 account for ~50% of patients with sarcomeric hypertrophic cardiomyopathy (HCM),[8,9] and are inherited in an autosomal dominant fashion (OMIM 115197). Patients with HCM can experience a variety of adverse clinical outcomes, including outflow tract obstruction, arrhythmias, heart failure, and sudden cardiac death.[8] Genetic variants in MYBPC3 consist of both truncating and nontruncating types. Found in healthy populations, truncating MYBPC3 variants result in a premature stop codon and cause HCM through complete LoF and haploinsufficiency at the transcript and protein level.[10,11,12,13] interpretation of these truncating variants as pathogenic is straightforward.[14]
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