ClinVar

Description

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.