Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000689040 | SCV000816676 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2019-11-27 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the TTN gene (p.Gly19523Valfs*8). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 568621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). 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. |
| Gene |
RCV001008202 | SCV001167968 | pathogenic | not provided | 2019-05-21 | criteria provided, single submitter | clinical testing | The c.53645delG pathogenic variant in the TTN gene has not been published as pathogenic or benign to our knowledge. c.53645delG causes a shift in reading frame starting at codon glycine 17882, changing it to a valine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Gly17882ValfsX8. This 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.53645delG 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). Moreover, the c.53645delG variant has not been observed in large population cohorts (Lek et al., 2016). |