Submissions for variant NM_005159.5(ACTC1):c.500T>C (p.Ile167Thr)

dbSNP: rs730880409

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157804	SCV000207734	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with a ACTC1-related disorder to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30681346)
Invitae	RCV000477476	SCV000550881	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2019-03-06	criteria provided, single submitter	clinical testing	In summary, this variant is a novel missense change with uncertain impact on protein function. 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. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ACTC1-related disease. This sequence change replaces isoleucine with threonine at codon 167 of the ACTC1 protein (p.Ile167Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149962	SCV003838199	uncertain significance	Cardiomyopathy	2022-03-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372625	SCV004071332	uncertain significance	Cardiovascular phenotype	2023-08-10	criteria provided, single submitter	clinical testing	The p.I167T variant (also known as c.500T>C), located in coding exon 3 of the ACTC1 gene, results from a T to C substitution at nucleotide position 500. The isoleucine at codon 167 is replaced by threonine, an amino acid with similar properties. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223818	SCV000280036	uncertain significance	not specified	2013-07-24	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. ACTC1 p.Ile167Thr Based on the data reviewed below, we consider this variant to be of uncertain significance. The variant is novel. As of December 28, 2011, no variation at codon 167 of ACTC1 has been reported in the literature (according to searches of PubMed and Google), in the Harvard Sarcomere Protein Gene Mutation Database, or in an ACTC1-specific mutation database curated by Johan den Dunnen and accessed through the Leiden Open Variation Database (http://www.dmd.nl/nmdb/home.php?select_db=ACTC1). Of note, pathogenic HCM variants have been reported at the two immediately adjacent amino acids: Pro166Ala (reported 2 times), and Tyr168Cys, which are present in the Harvard and Leiden databases with published references. This is a non-conservative amino acid substitution in which a nonpolar Isoleucine is replaced by a neutral, polar Threonine. The change is at a residue that is completely conserved across vertebrate species, as are the surrounding residues. In silico analysis with PolyPhen-2 predicts the variant to be benign. However, in silico analysis with SIFT and Mutation Taster predicts the variant to be disease-causing. GeneDx reports that the variant was absent in up to 100 presumably healthy individuals of Caucasian ancestry. The variant is not reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/), dbSNP (www.ncbi.nlm.nih.gov/SNP), or 1000 Genomes (http://browser.1000genomes.org/index.html) as of December 28, 2011. The ACTC1 gene product (cardiac alpha-actin) has a 99% identical isoform (skeletal alpha-actin), coded by ACTA1. These two proteins differ by only 4 out of 375 amino acids. In fact, they have overlapping functions: During fetal development cardiac alpha-actin serves as the isoform in skeletal muscle, and mature heart muscle contains both cardiac alpha-actin (80% of the total) and skeletal alpha-actin (20% of the total). Given the extensive overlap in function and amino acid sequence, data about skeletal alpha-actin (ACTA1) variants can help guide our assessment of the patient’s cardiac alpha-actin (ACTC1) variant. Pathogenic mutations in ACTA1 cause congenital skeletal myopathies, and variants in this protein are catalogued in a locus-specific database created by the Laing Molecular Neurogenetics Laboratory at the Western Australian Institute for Medical Research (http://www.waimr.uwa.edu.au/research/lovd.html). The database contains no variants at Ile167. However, mutations at several nearby residues (within 10 residues to either side) are reported to cause congenital skeletal myopathies: Gly160Cys, His163Asp, His163Tyr (possibly recessive), Val165Leu (reported 3 times), Val165Met, Ala172Glu (reported 2 times), and Ala172Gly.