ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.15346C>T (p.Arg5116Ter)

gnomAD frequency: 0.00001  dbSNP: rs1057518470
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414680 SCV000492135 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing The R3872X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3872X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, the R3872X variant is not located in the A-band nor the M-line region of titin, where the majority of pathogenic truncating variants have been reported.
Labcorp Genetics (formerly Invitae), Labcorp RCV001861434 SCV002167625 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg5116*) in the TTN gene. 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 (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with inclusion body myopathy (PMID: 28256728). ClinVar contains an entry for this variant (Variation ID: 373536). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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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