Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001089814 | SCV001245301 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2019-06-17 | criteria provided, single submitter | clinical testing | This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 320 of the TTN gene (c.67705_67706ins168), causing a frameshift at codon 22569 (p.Arg22569fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. 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 conditions. 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). 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. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). 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. |