Submissions for variant NM_001267550.2(TTN):c.669+1G>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003187561	SCV003856801	uncertain significance	Cardiovascular phenotype	2022-12-07	criteria provided, single submitter	clinical testing	The c.669+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the TTN gene. This exon is located in the Z-disk region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Truncating variants (a category that includes canonical splice site variants) in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with 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). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003779530	SCV004578515	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted 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: 2451865). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, internal data). 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, internal data). 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.