Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521925 | SCV000621676 | likely pathogenic | not provided | 2018-05-17 | criteria provided, single submitter | clinical testing | The c.70064_70068dupAAGTA likely pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant causes a shift in reading frame starting at codon serine 23357, changing it to a lysine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Ser23357LysfsX28. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.70064_70068dupAAGTA is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Finally, the c.70064_70068dupAAGTA variant is not observed in large population cohorts (Lek et al., 2016). |
| Invitae | RCV000810190 | SCV000950383 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-12-06 | criteria provided, single submitter | clinical testing | 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. 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 variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 452835). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Ser24998Lysfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |