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Recently, variants in a new disease gene, <jats:italic>ACTN2<\/jats:italic>, have been shown to cause distal myopathy. <jats:italic>ACTN2<\/jats:italic>, a gene previously only associated with cardiomyopathies, encodes alpha\u2010actinin\u20102, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha\u2010actinin\u20102 is to link actin and titin to the sarcomere Z\u2010disk. New <jats:italic>ACTN2<\/jats:italic> variants are continuously discovered; however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype\u2013phenotype correlations in <jats:italic>ACTN2<\/jats:italic>\u2010related diseases, actininopathies, persists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Functional characterization in C2C12 cell model of several <jats:italic>ACTN2<\/jats:italic> variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies. We assess the genotype\u2013phenotype correlations of actininopathies using clinical data from several patients carrying these variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha\u2010actinin\u20102 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do form alpha\u2010actinin\u20102 aggregates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The results suggest that alpha\u2010actinin\u20102 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein\u2010extending frameshift variants in <jats:italic>ACTN2<\/jats:italic> should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52154","type":"journal-article","created":{"date-parts":[[2024,8,3]],"date-time":"2024-08-03T03:53:59Z","timestamp":1722657239000},"page":"2392-2405","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Protein\u2010extending <scp><i>ACTN2<\/i><\/scp> frameshift variants cause variable myopathy phenotypes by protein aggregation"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7050-8688","authenticated-orcid":false,"given":"Johanna","family":"Ranta\u2010aho","sequence":"first","affiliation":[{"name":"Folkh\u00e4lsan Research Center  Haartmaninkatu 8 00290 Helsinki Finland"},{"name":"Department of Medical Genetics, Medicum University of Helsinki  Haartmaninkatu 8 Helsinki 00290 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