ClinVar

Description

The c.80694delA pathogenic mutation, located in coding exon 190 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 80694, causing a translational frameshift with a predicted alternate stop codon (p.K26898Nfs*9). This exon is located in the M-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This mutation (also referred to as K33395Nfs*9 (c.100185delA), p.K35963Nfs*9 (c.107889delA), p.K33394Nfs*9 (c.100185delA) in the literature) has been reported in the homozygous and compound heterozygous state with other truncating variants in TTN in association with skeletal muscle disease phenotypes including distal myopathy, centronuclear myopathy, and tibial muscular dystrophy (Hackman P et al. Neuromuscul. Disord., 2008 Dec;18:922-8; Ceyhan-Birsoy O et al. Neurology, 2013 Oct;81:1205-14; Evilä A et al. Ann. Neurol., 2014 Feb;75:230-40; Evilä A et al. Neuromuscul. Disord., 2016 Jan;26:7-15; Välipakka S et al. Neurol Genet, 2017 Dec;3:e204). This variant has also been detected in sudden death and dilated cardiomyopathy cohorts; however, details were not provided (Campuzano O et al. Int J Mol Sci, 2015 Oct;16:25773-87). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of DCM (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.