Submissions for variant NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)

gnomAD frequency: 0.00003  dbSNP: rs727504198

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000760496	SCV000226712	uncertain significance	not provided	2015-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV000560235	SCV000643133	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu13655*) 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 present in population databases (rs727504198, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive centronuclear myopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167788). This variant disrupts the Z and I bands of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000618763	SCV000737324	likely pathogenic	Cardiovascular phenotype	2023-01-06	criteria provided, single submitter	clinical testing	The p.E4590* variant (also known as c.13768G>T), located in coding exon 52 of the TTN gene, results from a G to T substitution at nucleotide position 13768. This changes the amino acid from a glutamic acid to a stop codon within coding exon 52. This exon is located in the I-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 has been reported in a subject referred for exome sequencing, but specific clinical information was limited (Connell PS et al. Circ Genom Precis Med, 2021 Feb;14:e003131). 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.
GeneDx	RCV000760496	SCV000890386	likely pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Reported as an incidental finding in a cohort of individuals undergoing clinical exome sequencing; however, the phenotype of the individual was not provided (Connell et al., 2021); This variant is associated with the following publications: (PMID: 23975875, 27625338, 27869827, 33226272)
Revvity Omics, Revvity	RCV000760496	SCV003824173	uncertain significance	not provided	2021-02-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003453148	SCV004183465	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2023-10-19	criteria provided, single submitter	clinical testing