{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T12:40:12Z","timestamp":1775306412268,"version":"3.50.1"},"reference-count":18,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The ACMG\/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (<jats:italic>VCL<\/jats:italic>) gene illustrates these challenges. Model organism data provide\u00a0evidence that loss of function of <jats:italic>VCL<\/jats:italic> may play a role in cardiomyopathy and aggregate case\u2010control studies suggest low penetrance.\u00a0<jats:italic>VCL<\/jats:italic> loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from &gt;18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with <jats:italic>VCL<\/jats:italic> loss\u2010of\u2010function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR]\u2009=\u20099.01; confidence interval [CI]\u2009=\u20094.93\u201316.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of <jats:italic>VCL<\/jats:italic> alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, <jats:italic>VCL<\/jats:italic> loss\u2010of\u2010function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.<\/jats:p>","DOI":"10.1002\/humu.24061","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T17:28:59Z","timestamp":1591723739000},"page":"1577-1587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy"],"prefix":"10.1155","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7459-6263","authenticated-orcid":false,"given":"Megan H.","family":"Hawley","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine  Cambridge 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Irving Medical Center  New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Garcia","sequence":"additional","affiliation":[{"name":"Invitae Corporation  San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa A.","family":"Grebe","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism, Department of Child Health, Phoenix Children's Hospital University of Arizona College of Medicine  Phoenix Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa A.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute Geisinger  Danville Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew S.","family":"Lebo","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine  Cambridge 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University of Arizona College of Medicine  Phoenix Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate L.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Vatta","sequence":"additional","affiliation":[{"name":"Invitae Corporation  San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roddy","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC University of Amsterdam  Amsterdam The Netherland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James S.","family":"Ware","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute Imperial College London  London UK"},{"name":"Cardiovascular Research Centre Royal Brompton and Harefield Hospitals NHS Foundation Trust  Harefield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Stanford University School of Medicine  Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hana","family":"Zouk","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine  Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Mason\u2010Suares","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine  Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Funke","sequence":"additional","affiliation":[{"name":"Laboratory for 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