Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003764696 | SCV004585857 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-07-29 | criteria provided, single submitter | clinical testing | 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). This sequence change creates a premature translational stop signal (p.Tyr18212*) 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 clinical features of TTN-related disorders (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 47092). 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, |
RCV000040362 | SCV000064053 | likely pathogenic | Primary dilated cardiomyopathy | 2015-10-08 | no assertion criteria provided | clinical testing | The p.Tyr15644X variant in TTN has not been previously reported in individuals w ith cardiomyopathy and was absent from large population studies. This nonsense v ariant leads to a premature termination codon at position 15644, which is predic ted to lead to a truncated or absent protein. Nonsense variants and other trunca ting variants in TTN are strongly associated with DCM if they impact the exons e ncoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon th at is highly expressed in the heart (Roberts 2015). The p.Tyr15644X variant is l ocated in A-band in the highly expressed exon 231. In summary, although addition al studies are required to fully establish its clinical significance, the p.Tyr1 5644X variant is likely pathogenic. |