ClinVar

Description

The TTN c.85267C>T variant is predicted to result in premature protein termination (p.Arg28423*). This variant was reported in five individuals with dilated cardiomyopathy (Table S IV, reported as chr2:178560865 in Bourfiss et al. 2022. PubMed ID: 36264615). The c.85267C>T variant is located in the A-band region of the TTN protein and several other premature stop variants in this exon have previously been reported to be pathogenic for recessive and dominant TTN-related disorders including dilated cardiomyopathy, centronuclear myopathy, and muscular dystrophy (Human Gene Mutation Database). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 95-100%; https://www.cardiodb.org/titin/titin_exon.php?id=327; Roberts A.M. et al. 2015. PMID: 25589632). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). Many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. In summary, the c.85267C>T, p.Arg28423* variant is pathogenic for both autosomal recessive and dominant TTN-related disorders. Of note, this variant is considered pathogenic for increased risk of TTN-related cardiac disorders, and also for autosomal recessive severe congenital titinopathies when in the presence of an additional loss-of-function TTN variant.