Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152508 | SCV000201683 | likely pathogenic | Primary dilated cardiomyopathy | 2013-06-05 | criteria provided, single submitter | clinical testing | The Gln1343X variant in TTN has not been reported in individuals with cardiomyop athy or in large population studies. This nonsense variant leads to a premature termination codon at position 1343, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly asso ciated with DCM and the majority occur in the A-band (Herman 2012, LMM unpublish ed data), while this variant occurs in nearby Z-disc. In summary, this variant i s likely to be pathogenic, though additional studies are required to fully estab lish its clinical significance. |
| Labcorp Genetics |
RCV001359440 | SCV001555310 | 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.Gln1343*) 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: 166322). 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. |
| Ambry Genetics | RCV002354352 | SCV002620587 | uncertain significance | Cardiovascular phenotype | 2019-08-26 | criteria provided, single submitter | clinical testing | The p.Q1297* variant (also known as c.3889C>T), located in coding exon 22 of the TTN gene, results from a C to T substitution at nucleotide position 3889. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This exon is located in the near 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 alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating 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;366:619-28; Roberts AM et al. Sci Transl Med. 2015;7:270ra6; Schafer S et al. Nat. Genet. 2017;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. |