Submissions for variant NM_001267550.2(TTN):c.89053A>T (p.Lys29685Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002858344	SCV003232995	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys29685*) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225998	SCV003922162	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Lys29685Ter variant in TTN was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 202275), in one individual with Salih myopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 202275). The p.Lys29685Ter variant in TTN has not been previously reported in individuals with Salih myopathy. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 29685, which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive Salih myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Salih myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).