Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000184276 | SCV000236899 | pathogenic | not provided | 2019-02-21 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000814982 | SCV000955422 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-11-27 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the TTN gene (p.Leu28825*). 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). 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: 202420). |
Rady Children's Institute for Genomic Medicine, |
RCV003335181 | SCV004046097 | likely pathogenic | TTN-Related Disorders | criteria provided, single submitter | clinical testing | This nonsense variant found in exon 326 of 363 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not been previously reported or functionally characterized in the literature to our knowledge. Loss-of-function variation in TTN is an established mechanism of disease (PMID: 22335739; 25589632). This variant occurs within the A-band of TTN. Previous analyses have shown that loss-of-function variants, especially within the A-band and I/A band junctions of TTN, are enriched in dilated cardiomyopathy cohorts compared to population controls (PMID: 26777568). The c.86474T>G (p.Leu28825Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.86474T>G (p.Leu28825Ter) variant is classified as Pathogenic. |