The ACTC1 gene has been associated with autosomal dominant hypertrophic cardiomyopathy (HCM) in at least 6 probands in 4 publications. Four unique variants (missense) with convincing evidence of pathogenicity have been reported in humans, including de novo inheritance with maternity and paternity confirmed in two cases and segregation with disease in 26 additional family members. ACTC1 was first associated with this disease in humans in 1999 (Mogensen et al, PMID 10330430). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is unknown. The ACTC1 gene was significantly enriched for missense variants in Walsh et al, 2016 (PMID 27532257). Overall, the gene was found to have an Odds Ratio of 8.59 (5.06-14.5) for HCM. This gene-disease association is supported by expression studies, in vitro functional assays, and an animal model. In summary, ACTC1 is definitively associated with autosomal dominant HCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Expert Panel and was approved on September 5, 2017 using SOP version 5. It was reevaluated on June 23, 2021. As a result of this reevaluation, the classification did not change and no additional evidence has been added.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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