Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825639 | SCV000967003 | likely pathogenic | Primary dilated cardiomyopathy | 2019-01-02 | criteria provided, single submitter | clinical testing | The p.Gln32415X variant in TTN has not been previously reported in individuals w ith DCM and was absent from large population studies. This nonsense variant lead s to a premature termination codon at position 32415, 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 impact the exons encoding for the A-ba nd (Herman 2012, Pugh 2014) and/or are located in an exon that is highly express ed in the heart (Roberts 2015). The p.Gln32415X variant is located in a highly e xpressed exon in the M-band. In summary, although additional studies are require d to fully establish its clinical significance, this variant meets criteria to b e classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2. |
| Labcorp Genetics |
RCV003768554 | SCV004574915 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln34983*) 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 premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 667024). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). 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. |