ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.87705C>G (p.Tyr29235Ter)

dbSNP: rs1575584918
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000801960 SCV000941766 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2020-10-27 criteria provided, single submitter clinical testing 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. 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). This variant has not been reported in the literature in individuals with TTN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Tyr29235*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825609 SCV000966954 likely pathogenic Primary dilated cardiomyopathy 2019-02-21 criteria provided, single submitter clinical testing The p.Tyr26667X variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 26667, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Tyr26667X variant is located in the A-band in a highly expressed exon. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2.

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