Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000808952 | SCV000949086 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2018-10-14 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Met125 amino acid residue in ACTC1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 17947298), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ACTC1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 125 of the ACTC1 protein (p.Met125Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. |
| Gene |
RCV001766689 | SCV001998203 | uncertain significance | not provided | 2019-11-12 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Ambry Genetics | RCV003166278 | SCV003854769 | uncertain significance | Cardiovascular phenotype | 2022-11-21 | criteria provided, single submitter | clinical testing | The p.M125T variant (also known as c.374T>C), located in coding exon 2 of the ACTC1 gene, results from a T to C substitution at nucleotide position 374. The methionine at codon 125 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |