Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000242484 | SCV000320320 | uncertain significance | Cardiovascular phenotype | 2015-10-27 | criteria provided, single submitter | clinical testing | The p.D159E variant (also known as c.477T>G), located in coding exon 3 of the ACTC1 gene, results from a T to G substitution at nucleotide position 477. The aspartic acid at codon 159 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. In addition, an alteration affecting the same amino acid, p.D159N (c.475G>A), was reported in an individual with dilated cardiomyopathy (DCM) who also had alterations in other cardiac-related genes (Pugh TJ et al. Genet Med. 2014;16(8):601-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| Invitae | RCV001297670 | SCV001486698 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2020-08-03 | 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. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 264401). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 159 of the ACTC1 protein (p.Asp159Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. |