ClinVar

Description

A variant of uncertain significance has been identified in the ACTC1 gene. The c.431 T>G (L144R) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and it was not observed in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The c.431 T>G variant occurs within the last 24 nucleotides of exon 3 and could be functionally significant at the protein or mRNA level. At the protein level, c.431 T>G results in the L144R non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This amino acid substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. At the mRNA level, in silico splice prediction programs predict that c.431 T>G does not impact the natural splice donor site at intron 3 but strongly activates an upstream cryptic splice donor site which may impact splicing. However, in the absence of functional mRNA studies, the physiological consequences of the c.431 T>G variant cannot be precisely determined. Furthermore, the majority of variants reported in the ACTC1 gene are missense changes (Stenson et al., 2014), indicating haploinsufficiency of ACTC1 may not be sufficient to cause cardiomyopathy.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.