ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.500T>C (p.Ile167Thr) (rs730880409)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157804 SCV000207734 likely pathogenic not provided 2011-12-09 criteria provided, single submitter clinical testing This missense change is denoted p.Ile167Thr (I167T) at the protein level, and c.500 T>C at the cDNA level. The Ile167Thr variant in the ACTC1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ile167Thr results in a non-conservative amino acid substitution of a non-polar Isoleucine with a neutral, polar Threonine at a position that is highly conserved throughout evolution. In silico analysis predicts Ile167Thr is disease-causing (Kumar P et al., 2009; Schwarz JM et al., 2010). Missense mutations in nearby codons (Pro166Ala, Tyr168Cys) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, Ile167Thr was not detected in up to 200 control alleles from individuals of Caucasian ancestry tested at GeneDx, indicating it is likely not a benign polymorphism in this population. With the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of Ile167Thr in the ACTC1 gene, although the evidence suggests it may be disease-causing. The variant is found in HCM panel(s).
Invitae RCV000477476 SCV000550881 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-03-06 criteria provided, single submitter clinical testing 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. 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. 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. 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.
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.

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