ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.73387del (p.Ala24463fs)

dbSNP: rs1553607425
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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 RCV000603947 SCV000731667 likely pathogenic Primary dilated cardiomyopathy 2017-05-31 criteria provided, single submitter clinical testing The p.Ala21895fs variant in TTN has not been previously reported in individuals with DCM or large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 2189 5 and leads to a premature termination codon 8 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Frameshift an d other truncating variants in TTN are strongly associated with DCM if they impa ct 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.Ala21895 fs variant is located in the A-band in the highly expressed exon 275. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Ala21895fs variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001855252 SCV002316206 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-05-18 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. ClinVar contains an entry for this variant (Variation ID: 517403). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala24463Profs*8) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.

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