ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 17 citations in OpenAlex.
- Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.Circulation · 2026Article
- Diffuse hypertrophic obstructive cardiomyopathy complicated by apical ventricular aneurysm and excessive left ventricular trabeculation: a case report.Frontiers in cardiovascular medicine · 2026Article
- Beyond the Left Atrium: Genetic and Renal Determinants of Atrial Fibrillation in Hypertrophic Cardiomyopathy.Korean circulation journal · 2025Article
- Evaluating Pathogenicity ofJournal of precision medicine (Amsterdam, Netherlands) · 2025Article
- Bringing into focus the central domains C3-C6 of myosin binding protein C.Frontiers in physiology · 2024Review
- An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2023Review
- Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy.Frontiers in cardiovascular medicine · 2023Review
- A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.Human molecular genetics · 2022Article
- Correspondence on "Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation" by Thompson et al.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Response to Suay-Corredera et al.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.The Journal of biological chemistry · 2021Article
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Authors and funding
19 authors at 13 institutions in 6 countries.
Funding
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.
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