Submissions for variant NM_001267550.2(TTN):c.6532C>T (p.Gln2178Ter)

dbSNP: rs1193046655

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497670	SCV000590728	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing	The Q2178X variant in the TTN gene has not been reported as a pathogenic or benign to our knowledge. The Q2178X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q2178X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Though truncating variants in TTN account for largest described genetic cause of dilated cardiomyopathy (Herman et al., 2012), these occur in the A-band. Whereas, the Q2178X variant is located elsewhere, in the I-band of TTN. Moreover, truncating variants in the TTN gene have been reported in approximately 3% of control alleles (Herman et al., 2012). Finally, in the absence of functional studies, the physiological consequence of this variant cannot be precisely determined.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851386	SCV002308312	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2178*) 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 (no rsID available, gnomAD 0.0009%). 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: 432949). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, 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.
Ambry Genetics	RCV002356817	SCV002655304	likely pathogenic	Cardiovascular phenotype	2021-10-29	criteria provided, single submitter	clinical testing	The p.Q2132* variant (also known as c.6394C>T), located in coding exon 27 of the TTN gene, results from a C to T substitution at nucleotide position 6394. This changes the amino acid from a glutamine to a stop codon within coding exon 27. 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 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). As such, this alteration is classified as likely pathogenic.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003327408	SCV004034982	likely pathogenic	Dilated cardiomyopathy 1G	2023-08-09	criteria provided, single submitter	clinical testing