ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.78178G>T (p.Glu26060Ter) (rs794729289)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184265 SCV000236888 pathogenic not provided 2013-07-03 criteria provided, single submitter clinical testing The E24419X mutation in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. E24419X 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. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, E24419X is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, E24419X was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in DCM panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000184265 SCV000344817 likely pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
Invitae RCV000703198 SCV000832086 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-07-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Glu26060*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 9,932 amino acids of the TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 202409). 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.

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