Submissions for variant NM_001267550.2(TTN):c.50375_50378del (p.Glu16792fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002448072	SCV002733497	likely pathogenic	Cardiovascular phenotype	2019-12-04	criteria provided, single submitter	clinical testing	The c.23180_23183delAAAG variant, located in coding exon 95 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 23180 to 23183, causing a translational frameshift with a predicted alternate stop codon (p.E7727Gfs*2). 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 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). As such, this alteration is classified as likely pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV003994434	SCV004812857	pathogenic	Dilated cardiomyopathy 1G	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change in TTN is a frameshift variant predicted to cause a premature stop codon, p.(Glu16792Glyfs*2), in constitutively expressed exon 268 (percentage splice in, PSI, 100%) in the A-band. High PSI truncating variants in TTN have a significant association with dilated cardiomyopathy (PMID: 31216868). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been identified in at least two probands with a phenotype consistent with dilated cardiomyopathy (Ambry Genetics; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PS4_Supporting.
GeneDx	RCV004785706	SCV005401636	likely pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); This variant is associated with the following publications: (PMID: 22335739)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005227755	SCV005863025	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu16792Glyfs*2) 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: 1789509). 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.