Submissions for variant NM_001267550.2(TTN):c.44364del (p.Tyr14789fs)

dbSNP: rs397517576

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040246	SCV000063937	likely pathogenic	Primary dilated cardiomyopathy	2012-03-19	criteria provided, single submitter	clinical testing	The Tyr12221fs variant (TTN) has not been previous reported, but has been identi fied in one individual with DCM tested by our laboratory. This variant is predic ted to cause a frameshift, which alters the protein's amino acid sequence beginn ing at codon 12221 and leads to a premature stop codon 15 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein (lo ss of function). Loss-of-function variants in TTN are common in patients with DC M (Herman 2012). In summary, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852831	SCV002215063	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-04-13	criteria provided, single submitter	clinical testing	This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 46976). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr14789Thrfs*15) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225926	SCV003922164	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Tyr14789ThrfsTer15 variant in TTN was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 284443), in two siblings with Salih myopathy. Familial exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 284443). The p.Tyr14789ThrfsTer15 variant in TTN has not been previously reported in individuals with Salih myopathy. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 46976) and has been interpreted with conflicting interpretations of pathogenicity. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 14789 and leads to a premature termination codon 15 amino acids downstream. This alteration is then 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).
Molecular Genetics, Royal Melbourne Hospital	RCV000040246	SCV004812880	likely pathogenic	Primary dilated cardiomyopathy	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in TTN is a frameshift variant predicted to cause a premature stop codon, p.(Tyr14789Thrfs*15), in constitutively expressed exon 240 (percentage splice in, PSI, 100%) in the I-band (proximal to the A-band). High PSI truncating variants in TTN have a significant association with dilated cardiomyopathy (PMID: 31216868). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with dilated cardiomyopathy (PMID: 31983221, 36277766). The variant has been reported to segregate with TTN-related myopathy with a second TTN variant in a single family (ClinVar: SCV003922164.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PP1, PS4_Supporting.