Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000157775 | SCV000207705 | uncertain significance | not provided | 2017-06-08 | criteria provided, single submitter | clinical testing | The T8A variant of uncertain significance in the ACTC1 gene has not been published as pathogenic or benign to our knowledge. This variant is a 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 substitution also occurs at a position that is conserved across species. In silico analysis predicts T8A is probably damaging to the protein structure/function. Moreover, T8A is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, T8A has been identified in another individual referred for HCM testing at GeneDx; however, this individual was found to carry additional cardiogenetics variants, and segregation data is absent due to insufficient participation by informative family members. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign. |
| Invitae | RCV001319568 | SCV001510316 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 8 of the ACTC1 protein (p.Thr8Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 180755). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| Ambry Genetics | RCV002426769 | SCV002731730 | uncertain significance | Cardiovascular phenotype | 2021-01-04 | criteria provided, single submitter | clinical testing | The p.T8A variant (also known as c.22A>G), located in coding exon 1 of the ACTC1 gene, results from an A to G substitution at nucleotide position 22. The threonine at codon 8 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |