Submissions for variant NM_001267550.2(TTN):c.46272C>A (p.Tyr15424Ter)

dbSNP: rs879139686

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044590	SCV001208395	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr15424*) 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 (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant dilated cardiomyopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 842206). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017779	SCV004847935	likely pathogenic	Primary dilated cardiomyopathy	2019-01-18	criteria provided, single submitter	clinical testing	The p.Tyr12856X variant in TTN has not been previously reported in individuals with DCM and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 12856, 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.Tyr12856X variant is located in a highly expressed exon in the I-band. In addition, computational tools predict the possible creation of a novel splice site, but their accuracy is unknown. 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.