ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.48283C>T (p.Arg16095Ter) (rs374140736)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184218 SCV000236840 pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing The R14454X pathogenic variant in the TTN gene, also denoted as R13527X due to the use of an alternate transcript, has been previously reported in association with DCM (Norton et al., 2013; Chanavat et al., 2016). Norton et al. (2013) identified this variant in six relatives from one family; three relatives with DCM, one relative who died at age 69 with mild systolic dysfunction but without left ventricular enlargement, having suffered an myocardial infarction in her 50’s, as well as two other relatives in their 20’s with no evidence of DCM. Chanavat et al. (2016) also detected R14454X in an individual with DCM who also harbored a nonsense variant in the FLNC gene, although further segregation studies were not described. R14454X 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 et al., 2012). However, R14454X is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, R14454X is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000621940 SCV000737091 pathogenic Cardiovascular phenotype 2018-12-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000184218 SCV000927899 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
Invitae RCV000796818 SCV000936346 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-05-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg16095*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs374140736, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and segregated with dilated cardiomyopathy in a family (PMID: 23418287). This variant is also known as c.40579C>T Arg13527stop in the literature. ClinVar contains an entry for this variant (Variation ID: 202371). 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). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256709 SCV001433112 pathogenic Dilated cardiomyopathy 1A 2020-01-07 criteria provided, single submitter clinical testing

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