Submissions for variant NM_001267550.2(TTN):c.101098_101099insT (p.Asp33700fs)

dbSNP: rs869312122

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209694	SCV000189796	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558029	SCV000639025	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-09	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the TTN gene (p.Asp33700Valfs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2,292 amino acids of the TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. A different truncating  variant at this codon p.Asp33700Valfs*13 has been reported in the literature in an individual affected with dilated cardiomyopathy (DCM) (PMID: 25589632). However, truncating variants in the M-band have not been associated with DCM and the authors did not present any further evidence to confirm that this variant is causative of isolated DCM instead of an incidental finding. This variant is found in the M-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the M-band of TTN previously reported in patients affected with various forms of myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209694	SCV004847675	likely pathogenic	Primary dilated cardiomyopathy	2019-04-12	criteria provided, single submitter	clinical testing	The p.Asp31132ValfsX13 variant in TTN has been reported in 1 individual with DCM (Roberts 2015) and was absent from large population studies. It has been reported in ClinVar (Variation ID #223390). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 31132 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band (Herman 2012, Pugh 2014 , Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Asp31132ValfsX13 variant is located in a highly expressed exon in the M-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.