Submission Details

ACTC1 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). ACTC1 was originally evaluated for DCM by the ClinGen DCM GCEP on 5/8/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 4/4/2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.

Human genetic evidence supporting this gene-disease relation includes case-level data and segregation data. At least 11 variants, all missense, have been reported in humans with DCM (Olson, et al 1998, PMID: 9563954; Nguyen, et al 2021, PMID: 34011823; Pugh, et al 2014, PMID: 24503780; Vasilescu et al 2018, PMID: 3038488; Lakdawala, et al 2012, PMID: 22464770; Frank, et al 2019; PMID: 31430208; Acuna-Ochoa, et al 2024, PMID: 39759977). Nine of these variants were scored. Two of the eleven were not scored, as they were accounted for in a case control cohort, which showed ACTC1 variants enriched in a cohort of 1498 DCM patients referred for clinical genetic testing compared to ExAc (Mazzarotto, 2020; PMID: 31983221). This was the only case control study that was scored.

Olson et al, 1998 found that Arg312His and Glu361Gly segregated in two DCM families (PMID: 9563954). One family showed segregation in an affected parent and two affected children. A third genotype positive child did not have DCM. The second family had a variant segregating in an affected father and child. Another child and the father’s sister both the rare variant and left ventricular dilatation. One study of a large family identified the presence of an ACTC1 variant, Gly247Asp, in 15 individuals with atrial septal defect (ASD) and/or DCM (Frank et al, 2019, PMID: 31430208). The variant was absent in 63 unaffected individuals. Five of the 15 individuals had ASD and DCM, while one individual had DCM without ASD. Those with DCM were older individuals. Some older individuals with the variant did not have DCM, but no younger individuals with the variant had DCM, suggesting that there may be age-related penetrance. LOD score was not sufficient to yield points for segregation but this may be an underestimate since phenotypic data was taken from a table and individuals were not delineated in the pedigree. The rare p.Ala222Thr variant was found to be de novo in a 1 year old male with severe DCM (Acuna-Ochoa, et al 2024, PMID: 39759977).

In addition, this gene-disease relationship is supported by experimental evidence, including expression data and animal models. There are functional studies in mutant cells that implicate ACTC1 in the pathology of heart disease (Debold et al, 2010, PMID: 19799913; Frank et al, 2019, PMID: 31430208). There are multiple animal models including knock-out mice and zebrafish and transgenic mouse models for ACTC1 mutations previously reported in affected individuals (Abdelwahid et al, 2004, PMID: 14605248; Song et al, 2010, PMID: 20600154; Glenn et al, 2012, PMID: 22751927; Kumar et al, 1997, PMID: 9114002; Wilkinson et al, 2015, PMID: 26432839). Frank et al, 2019 showed that cardiac tissue from Gly247Asp carriers had increased Z-band structural disarray, increased apoptosis, sarcomeric disarray, and myofibrillar degeneration compared to control hearts and DCM hearts. The knock-out studies showed DCM-like phenotypes, with findings such as abnormal histology, apoptosis in the ventricles, enlarged ventricular cavities, while there were no significant differences between heterozygotes and wild type. Transgenic mice did not show a phenotype until stress was introduced. Wilkinson et al (2015, PMID: 26432839) showed that transgenic mice (Glu361Gly) that were chronically stressed showed contractile dysfunction and reduced EF and cardiac output. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on April 4, 2025 (SOP Version 10).