Submissions for variant NM_001267550.2(TTN):c.81886del (p.Glu27296fs)

dbSNP: rs727503557

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152204	SCV000200963	likely pathogenic	Primary dilated cardiomyopathy	2014-07-01	criteria provided, single submitter	clinical testing	The Glu24728fs variant in TTN has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This variant is predicted to c ause a frameshift, which alters the protein?s amino acid sequence beginning at p osition 24728 and leads to a premature termination codon 54 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM , particularly if they are located in the exons encoding for the A-band region o f the protein (Herman 2012, Pugh 2014), where this variant is located. In summar y, although additional studies are required to fully establish its clinical sign ificance, the Glu24728fs variant is likely pathogenic.
GeneDx	RCV000184341	SCV000236966	pathogenic	not provided	2021-06-15	criteria provided, single submitter	clinical testing	Has not been previously reported as pathogenic or benign to our knowledge; Reported in ClinVar (ClinVar Variant ID# 165801; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764932	SCV004589481	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu27296Lysfs*54) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8696 amino acid(s) of the TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 165801). 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.