Submissions for variant NM_005159.5(ACTC1):c.968C>T (p.Ala323Val)

dbSNP: rs730880404

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157799	SCV000207729	pathogenic	not provided	2014-01-26	criteria provided, single submitter	clinical testing	p.Ala323Val (GCT>GTT): c.968 C>T in exon 6 of the ACTC1 gene (NM_005159.4). The A323V mutation in the ACTC1 gene has been reported in one patient with HCM (Maron B et al., 2012). Maron et al. identified A323V in an 18 year old male with HCM who harbored another mutation in the MYBPC3 gene and had a family history of sudden cardiac death. This study did not observed this mutation in 300 control chromosomes. Additionally, A323V was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A323V mutation is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The A323 residue is highly conserved across species. Mutations in nearby residues (R314H, A333P) have been reported in association with cardiomyopathy further supporting the functional importance of this region of the protein. In summary, A323V in the ACTC1 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Center for Human Genetics, University of Leuven	RCV000768495	SCV000886800	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000819426	SCV000960085	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the ACTC1 protein (p.Ala323Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21839045, 25239116, 28790153; Invitae). ClinVar contains an entry for this variant (Variation ID: 180771). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ACTC1 protein function. 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000768495	SCV001156282	likely pathogenic	Hypertrophic cardiomyopathy	2018-05-02	criteria provided, single submitter	research	The ACTC1 Ala323Val has been reported previously in a HCM proband carrying another variant in a sarcomere gene, the proband was reported to have a family history of sudden cardiac death (Maron MS, et al., 2012). The variant has also been identified by another laboratory in at least 4 HCM probands and 2 family members (Genedx, personal communication). ACTC1 Ala323Val is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with a family history of HCM. The variant was found to segregate with disease in an uncle and first cousin-once removed. A second variant (MYL3 Ala75Asp) was also identified in the cousin but did not segregate to the proband or uncle. Computational tools predict this variant to have a deleterious effect (SIFT: "Deleterious"; MutationTaster: Disease-causing"; CADD score: 25.4). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in at least 2 HCM probands (PS4_supporting), in silico tools predict it to be deleterious (PP3), segregates with multiple affected family members (PP1_moderate) and is rare in the general population (PM2), therefore we classify ACTC1 Ala323Val as "likely pathogenic ".
Ambry Genetics	RCV002372028	SCV002690549	uncertain significance	Cardiovascular phenotype	2018-08-02	criteria provided, single submitter	clinical testing	The p.A323V variant (also known as c.968C>T), located in coding exon 5 of the ACTC1 gene, results from a C to T substitution at nucleotide position 968. The alanine at codon 323 is replaced by valine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) and was reported once in a subject with an alteration in another cardiac-related gene (Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10(4)). 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.