Submissions for variant NM_005159.5(ACTC1):c.740G>A (p.Gly247Asp)

dbSNP: rs1566967399

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770514	SCV000901959	likely pathogenic	Cardiomyopathy	2017-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216367	SCV001388163	pathogenic	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 247 of the ACTC1 protein (p.Gly247Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with atrial septal defect and/or dilated cardiomyopathy (PMID: 31430208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 626827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACTC1 protein function. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 31430208, 31434612). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002386332	SCV002671255	pathogenic	Cardiovascular phenotype	2022-01-21	criteria provided, single submitter	clinical testing	The p.G247D pathogenic mutation (also known as c.740G>A), located in coding exon 4 of the ACTC1 gene, results from a G to A substitution at nucleotide position 740. The glycine at codon 247 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been shown to segregate with disease in a family with atrial septal defects and dilated cardiomyopathy (Frank D et al. Circ Genom Precis Med, 2019 08;12:e002491). Functional and structural studies have suggested this alteration disrupts actin polymerization, which may impair contractility and have a deleterious impact on other cellular processes (Rangrez AY et al. Biochem Biophys Res Commun, 2019 10;518:500-505). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.