Submissions for variant NM_001267550.2(TTN):c.101227C>T (p.Arg33743Ter)

gnomAD frequency: 0.00001  dbSNP: rs794729305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184287	SCV000236910	likely pathogenic	not provided	2018-01-30	criteria provided, single submitter	clinical testing	The R32102X likely pathogenic variant (also denoted R31175X due to the use of an alternate transcript) in the TTN gene has been reported previously in association with dilated cardiomyopathy (DCM) and was found to segregate with disease in three individuals from one family who underwent whole exome sequencing (Norton et al., 2013). The R32102X variant is not observed in large population cohorts (Lek et al., 2016). R32102X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Nevertheless, R32102X is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). R32102X is located in the M-band of titin, where other truncating variants have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Lastly, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012).
Ambry Genetics	RCV000621263	SCV000735857	likely pathogenic	Cardiovascular phenotype	2024-01-08	criteria provided, single submitter	clinical testing	The p.R24678* variant (also known as c.74032C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 74032. This changes the amino acid from an arginine to a stop codon within coding exon 185. 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 alteration (also referred to as NM_133378.4:c.93523C>T, p.R31175*, Arg31175stop, and NM_001267550:c.101227C>T, p.Arg33743*) has been reported in three affected individuals from a family with with dilated cardiomyopathy (DCM), and has also been detected in an individual referred for DCM genetic testing and in a peripartum cardiomyopathy cohort (Norton N et al. Circ Cardiovasc Genet, 2013 Apr;6:144-53; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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 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 majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Invitae	RCV000706242	SCV000835281	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg33743*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal dominant dilated cardiomyopathy (PMID: 23418287, 30847666, 33874732). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg31175*. ClinVar contains an entry for this variant (Variation ID: 202429). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500557	SCV002811455	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-07-20	criteria provided, single submitter	clinical testing