Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000609399 | SCV000731353 | uncertain significance | not specified | 2017-01-06 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met178Leu variant in ACTC1 has been identified via exome sequencing in 1 Caucasian family with Atrial Septal Defect. The variant was present in 4 affected individuals an d 1 obligate carrier and was not absent in the one unaffected individual tested (Greenway 2014). This variant was absent from large population studies. Computat ional prediction tools and conservation analysis are suggest that the p.Met178Le u variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The ACTC1 gene has previously been associated with ASD (Matson 2008) but the overall data linking this gene to ASD is still li mited. Therefore, while there is some suspicion that the Met178Leu variant caus es ASD its clinical significance is uncertain. |
| Invitae | RCV001302582 | SCV001491796 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2022-05-22 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 178 of the ACTC1 protein (p.Met178Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with isolated secundum atrial septal defect (PMID: 24461919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 517203). 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 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 | RCV002343165 | SCV002640794 | uncertain significance | Cardiovascular phenotype | 2021-12-01 | criteria provided, single submitter | clinical testing | The p.M178L variant (also known as c.532A>T), located in coding exon 3 of the ACTC1 gene, results from an A to T substitution at nucleotide position 532. The methionine at codon 178 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in several affected members of a family with atrial septal defect (Greenway SC et al. Can J Cardiol, 2014 Feb;30:181-7). This amino acid position is highly conserved in available vertebrate species. 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. |
| Fulgent Genetics, |
RCV001302582 | SCV002814434 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2021-07-29 | criteria provided, single submitter | clinical testing |