Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812451 | SCV001472050 | likely pathogenic | not provided | 2020-08-07 | criteria provided, single submitter | clinical testing | The TTN c.82208C>G; p.Ser27403Ter variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon in exon 327 and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Exon 327 is spliced into 100% of TTN transcripts and encodes a segment of the A-band, a critical region of the TTN protein that interacts with myosin and which is disproportionately enriched with truncating variants in individuals affected with dilated cardiomyopathy (Roberts 2015, Schafer 2017). Based on available information, the p.Ser27403Ter variant is considered to be likely pathogenic. References: Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. Roberts AM et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015; 7(270): 270ra6. Schafer S et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet. 2017;49(1):46-53. |
| Invitae | RCV001871676 | SCV002257068 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2021-10-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser27403*) 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: 993722). 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. |