Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001349789 | SCV001544149 | 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 creates a premature translational stop signal (p.Glu497*) 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 observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with arrhythmia and/or dilated cardiomyopathy (PMID: 30061524, 31251381, 31983221); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 1045386). 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). This variant is located in the Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). 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. |
| Laboratory for Molecular Medicine, |
RCV004017821 | SCV004848230 | likely pathogenic | Primary dilated cardiomyopathy | 2018-07-25 | criteria provided, single submitter | clinical testing | The p.Glu497X variant in TTN has not been previously reported in individuals with DCM and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 497, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Glu497X variant is located in Z-band in the highly expressed exon 9. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu497X variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2. |