ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.56647+1G>A

dbSNP: rs397517624
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040383 SCV000064074 likely pathogenic Primary dilated cardiomyopathy 2019-09-18 criteria provided, single submitter clinical testing The 48943+1G>A variant in TTN has not been reported in the literature nor previously identified by our laboratory. This variant has not been identified in a very large and broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This variant occurs in the invariant region (+/- 1, 2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). In summary, this variant is likely to be pathogenic, though segregation studies and functional analyses are required to fully establish the pathogenicity of this variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001230770 SCV001403263 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2020-02-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 290 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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: 47113). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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