{"doi":"10.1101/2020.11.29.402974","title":"Computational prediction of protein subdomain stability in <i>MYBPC3</i> enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation","abstract":"Abstract Purpose Variants 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. Methods Among 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. 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 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. Conclusions STRUM enables clinical risk stratification of patients with HCM and a MYBPC3 VUS and has the capacity to improve prognostic predictions and clinical decision making.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131732,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":244331,"name":"Adam Helms","orcid":"0000-0002-0234-6430","position":1,"is_corresponding":false},{"id":586473,"name":"Anamika Kannan","orcid":null,"position":2,"is_corresponding":false},{"id":282071,"name":"Jaime Yob","orcid":"0000-0002-7206-6215","position":3,"is_corresponding":false},{"id":244336,"name":"Neal K. Lakdawala","orcid":"0000-0001-6458-5421","position":4,"is_corresponding":false},{"id":244330,"name":"Samuel G. Wittekind","orcid":"0000-0003-3192-0646","position":5,"is_corresponding":false},{"id":232958,"name":"Alexandre C. Pereira","orcid":"0000-0002-7782-5540","position":6,"is_corresponding":false},{"id":232951,"name":"Daniel Jacoby","orcid":"0000-0002-9182-275X","position":7,"is_corresponding":false},{"id":244333,"name":"Steven D. Colan","orcid":"0000-0002-7941-0947","position":8,"is_corresponding":false},{"id":3451,"name":"Euan A. Ashley","orcid":"0000-0001-9418-9577","position":9,"is_corresponding":false},{"id":244332,"name":"Sara Saberi","orcid":"0000-0003-4473-6725","position":10,"is_corresponding":false},{"id":230115,"name":"James S. Ware","orcid":"0000-0002-6110-5880","position":11,"is_corresponding":false},{"id":244335,"name":"Jodie Ingles","orcid":"0000-0002-4846-7676","position":12,"is_corresponding":false},{"id":244334,"name":"Christopher Semsarian","orcid":"0000-0001-6441-274X","position":13,"is_corresponding":false},{"id":232952,"name":"Michelle Michels","orcid":"0000-0001-6432-0431","position":14,"is_corresponding":false},{"id":282072,"name":"Francesco Mazzarotto","orcid":"0000-0002-6159-9980","position":15,"is_corresponding":false},{"id":232950,"name":"Iacopo Olivotto","orcid":"0000-0003-1751-9266","position":16,"is_corresponding":false},{"id":232956,"name":"Carolyn Y. Ho","orcid":"0000-0002-7334-7924","position":17,"is_corresponding":false},{"id":5580,"name":"Sharlene M. Day","orcid":"0000-0001-9802-7188","position":18,"is_corresponding":false},{"id":586474,"name":"SHaRe investigators","orcid":null,"position":19,"is_corresponding":false},{"id":282067,"name":"Andrea D. Thompson","orcid":"0000-0001-8798-2024","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}