ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter) (rs727504198)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618763 SCV000737324 likely pathogenic Cardiovascular phenotype 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000760496 SCV000226712 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000760496 SCV000890386 likely pathogenic not provided 2018-03-30 criteria provided, single submitter clinical testing The E12014X likely pathogenic variant in the TTN gene has not been published as pathogenic or benign to our knowledge. This variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). The E12014X variant is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the E12014X variant is located in one of the constitutive exons in the distal I-band region, and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Schafer et al., 2017; Rahual C. Deo, 2016).In summary, E12014X in the TTN gene is interpreted as a likely pathogenic variant.
Invitae RCV000560235 SCV000643133 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-01-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Glu13655*). 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 conditions. ClinVar contains an entry for this variant (Variation ID: 167788). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.