PurposeVariants in MYBPC3 causing loss-of-function are the most common cause of 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 improve clinical risk stratification of patients with HCM and a MYBPC3 VUS.MethodsAmong 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry, 120 unique missense VUSs 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 to 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.ConclusionsSTRUM enables clinical risk stratification of patients with HCM and a MYBPC3 VUS and has the capacity to improve prognostic predictions and clinical decision making.
Purpose Variants 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. Methods Among 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. Results We 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. Conclusion STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.
Introduction: Patients with HCM and a pathogenic sarcomere variant have a higher risk of adverse clinical outcomes compared to those without a sarcomere gene variant. Pathogenic truncating variants in MYBPC3 (encoding cardiac myosin binding protein C, MYBP-C) cause loss-of-function and are the most common genetic cause of HCM. However, a substantial number of patients carry missense variants in MYBPC3 that cannot be clearly classified as either pathogenic or benign. Interpretation of these variants of uncertain significance (VUS) remain a significant challenge. Hypothesis: We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on subdomain protein folding, will enable clinical risk stratification of patients with HCM and a MYBPC3 VUS. Methods and Results: Among the 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry (SHaRe), 19 unique missense pathogenic variants and 120 missense VUSs in MYBPC3 were identified. Within SHaRe and GnomAD, 110 benign missense variants (allele frequency > 4e-05) were identified. Following structural modeling of each MyBP-C domain, variants were predicted to cause subdomain misfolding if ΔΔG < = -1.2 kcal/mol (STRUM+). 93% of benign variants were predicted to be STRUM (-). Time-event analysis for an overall composite clinical endpoint [defined as the first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation (AF), or stroke] demonstrated that patients carrying a STRUM+ MYBPC3 VUS exhibited a higher rate of adverse events compared to those with a STRUM- VUS (Hazard Ratio=2.29, P=0.0282). Of the 120 missense VUSs, 34 (28%) were STRUM+. In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants predicted to cause subdomain misfolding. Conclusions: STRUM is capable of clinically risk stratifying HCM patients with a MYBPC3 VUSs . These findings support the routine use of STRUM in variant interpretation algorithms and clinical decision making.
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