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

dbSNP: rs1553607425

Total submissions: 2

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	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 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. This variant is not present in population databases (ExAC no frequency). 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.