ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.62909dup (p.Glu20971fs) (rs876657666)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000216412 SCV000271278 likely pathogenic Primary dilated cardiomyopathy 2015-02-13 criteria provided, single submitter clinical testing The p.Glu18403fs variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 18403 and leads to a premature termination codon 4 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Frameshift and other truncating variants in TTN are strongly associ ated with DCM, particularly if they are located in the exons encoding for the A- band region of the protein (Herman 2012, Pugh 2014), where this variant is locat ed. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu18403fs variant is likely pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732221 SCV000860144 likely pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000732221 SCV000927501 likely pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing
Invitae RCV000795052 SCV000934493 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-11-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Glu20971Argfs*4). 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. 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). 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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