Submissions for variant NM_001267550.2(TTN):c.97972C>T (p.Arg32658Ter)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003310301	SCV004000743	likely pathogenic	Cardiovascular phenotype	2023-04-16	criteria provided, single submitter	clinical testing	The p.R23593* variant (also known as c.70777C>T), located in coding exon 178 of the TTN gene, results from a C to T substitution at nucleotide position 70777. This changes the amino acid from an arginine to a stop codon within coding exon 178. This exon is located in the A-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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 A-band are the most common cause of dilated cardiomyopathy (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). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (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.
PreventionGenetics, part of Exact Sciences	RCV004529618	SCV004107699	likely pathogenic	TTN-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The TTN c.97972C>T variant is predicted to result in premature protein termination (p.Arg32658*). This variant occurs within the A-band region of the titin protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman DS et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts AM et al. 2015. PubMed ID: 25589632; Herman DS et al. 2012. PubMed ID: 22335739). To our knowledge, this variant has not been reported in the literature nor have other truncating variants in this exon been reported to be pathogenic for TTN-related disorders (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer S et al. 2017. PubMed ID: 27869827). In addition, truncating TTN mutations have also been associated with congenital myopathy (Ceyhan-Birsoy O et al. 2013. PubMed ID: 23975875). Therefore, the c.97972C>T (p.Arg32658*) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003777131	SCV004583797	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-07-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg32658*) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 2562241). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017977	SCV004847603	likely pathogenic	Primary dilated cardiomyopathy	2019-01-25	criteria provided, single submitter	clinical testing	The p.Arg30090X variant in TTN has not been reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 30090, which is predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band (Herman 2012, Pugh 2014, Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Arg30090X variant is located in the A-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.