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Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.<\/jats:p>","DOI":"10.3390\/ijms25073807","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T11:11:09Z","timestamp":1712229069000},"page":"3807","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5344-6573","authenticated-orcid":false,"given":"Alexandra","family":"P\u00e9rez-Serra","sequence":"first","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Toro","sequence":"additional","affiliation":[{"name":"Medicine Department, School of Medicine, Cadiz University, 11003 Cadiz, Spain"},{"name":"Research Unit, Biomedical Research and Innovation Institute of Cadiz (INiBICA), Puerta del Mar University Hospital, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefan\u00eda","family":"Martinez-Barrios","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands"},{"name":"Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de D\u00e9u Hospital de Barcelona, 08950 Barcelona, Spain"},{"name":"Arr\u00edtmies Pedi\u00e0triques, Cardiologia Gen\u00e8tica i Mort Sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Iglesias","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3179-8372","authenticated-orcid":false,"given":"Anna","family":"Fernandez-Falgueras","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-0913","authenticated-orcid":false,"given":"Mireia","family":"Alcalde","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Coll","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Puigmul\u00e9","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernat","family":"del Olmo","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0424-6393","authenticated-orcid":false,"given":"Elena","family":"Arbelo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands"},{"name":"Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-1756","authenticated-orcid":false,"given":"Sergi","family":"Cesar","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands"},{"name":"Pediatric Arrhythmias, Inherited Cardiac 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University Hospital, School of Medicine, University of Cadiz, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5662-8302","authenticated-orcid":false,"given":"Josep","family":"Brugada","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands"},{"name":"Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-8904","authenticated-orcid":false,"given":"Georgia","family":"Sarquella-Brugada","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands"},{"name":"Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de D\u00e9u Hospital de Barcelona, 08950 Barcelona, Spain"},{"name":"Arr\u00edtmies Pedi\u00e0triques, Cardiologia Gen\u00e8tica i Mort Sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, 08950 Barcelona, Spain"},{"name":"Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Brugada","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain"},{"name":"Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5298-5276","authenticated-orcid":false,"given":"Oscar","family":"Campuzano","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI-CERCA), Parc Hospitalari Mart\u00ed i Juli\u00e0, Edifici M2, 17190 Salt, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"2023 ESC Guidelines for the management of cardiomyopathies","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1093\/europace\/euac030","article-title":"European Heart Rhythm Association (EHRA)\/Heart Rhythm Society (HRS)\/Asia Pacific Heart Rhythm Society (APHRS)\/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases","volume":"24","author":"Wilde","year":"2022","journal-title":"Europace"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e002789","DOI":"10.1161\/CIRCGEN.119.002789","article-title":"Evaluation of Clinical Practices Related to Variants of Uncertain Significance Results in Inherited Cardiac Arrhythmia and Inherited Cardiomyopathy Genes","volume":"13","author":"Muller","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1161\/CIRCULATIONAHA.120.053033","article-title":"An Evidence-Based Assessment of Genes in Dilated Cardiomyopathy","volume":"144","author":"Jordan","year":"2021","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e000092","DOI":"10.1161\/HCG.0000000000000092","article-title":"Interpreting Incidentally Identified Variants in Genes Associated with Heritable Cardiovascular Disease: A Scientific Statement from the American Heart Association","volume":"16","author":"Landstrom","year":"2023","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Asatryan, B., Shah, R.A., Sharaf Dabbagh, G., Landstrom, A.P., Darbar, D., Khanji, M.Y., Lopes, L.R., van Duijvenboden, S., Muser, D., and Lee, A.M. (2023). Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank. JACC Heart Fail., ahead of print.","DOI":"10.1016\/j.jchf.2023.07.023"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1161\/CIRCULATIONAHA.123.064847","article-title":"Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study","volume":"148","author":"Hofmeyer","year":"2023","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1038\/s41431-023-01394-w","article-title":"The next step toward personalized recommendations for genetic cardiomyopathies","volume":"31","author":"Stroeks","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Campuzano, O., Sarquella-Brugada, G., Fernandez-Falgueras, A., Coll, M., Iglesias, A., Ferrer-Costa, C., Cesar, S., Arbelo, E., Garc\u00eda-\u00c1lvarez, A., and Jord\u00e0, P. (2020). 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