ClinVar

Description

The p.R145Q variant (also known as c.434G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 434. The arginine at codon 145 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), although in some cases it co-occurred with alterations in TNNI3 or other cardiac-related genes (Kimura A et al. Nat Genet. 1997;16:379-82; Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Berge KE et al. Clin Genet. 2014;86:355-60; Wang J et al. Eur J Heart Fail. 2014;16:950-7; Kim HY et al. J Clin Med, 2020 Jun;9:[Epub ahead of print]). This variant was reported to co-segregate with disease in two families, including one family with a pair of apparently homozygous affected siblings (Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Al-Shafai KN et al. Mol Genet Genomic Med, 2021 Jul;9:e1709). In vitro functional studies indicate this alteration results in reduced intrinsic inhibitory activity, increased calcium sensitivity of myofibrillar ATPase activity and increased force generation of skinned muscle fibers (Takahashi-Yanaga F et al. J Mol Cell Cardiol. 2001;33:2095-107). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear.