An Update on Reported Variants in the Skeletal Muscle -Actin () Gene.

The gene encodes skeletal muscle alpha-actin, which forms the core of the sarcomeric thin filament in adult skeletal muscle. ACTA1 represents one of six highly conserved actin proteins that have all been associated with human disease. The first 15 pathogenic variants in were reported in 1999, which expanded to 177 in 2009. Here, we update on the now 607 total variants reported in LOVD, HGMD, and ClinVar, which includes 343 reported pathogenic/likely pathogenic (P/LP) variants. We also provide suggested -specific modifications to ACMG variant interpretation guidelines based on our analysis of known variants, gnomAD reports, and pathogenicity in other actin isoforms. Using these criteria, we report a total of 447 P/LP variants. From a clinical perspective, the number of reported disease phenotypes has grown from five to 20, albeit with some overlap. The vast majority (74%) of variants cause nemaline myopathy (NEM), but there are increasing numbers that cause cardiomyopathy and novel phenotypes such as distal myopathy. We highlight challenges associated with identifying genotype-phenotype correlations for . Finally, we summarize key animal models and review the current state of preclinical treatments for disease. This update provides important resources and recommendations for the study and interpretation of variants.