Submissions for variant NM_001267550.2(TTN):c.81340_81344del (p.Lys27114fs)

dbSNP: rs886038928

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000254081	SCV000319212	likely pathogenic	Cardiovascular phenotype	2013-11-13	criteria provided, single submitter	clinical testing	​The c.73636_73640delAAGAA likely pathogenic variant, located in coding exon 274 of the TTN gene, results from a deletion of five nucleotides between positions 73636 and 73640, causing a translational frameshift with a predicted alternate stop codon. Frameshift alterations resulting in a truncated protein substantially alter protein structure, and this variant therefore meets ACMG criteria for classification as a mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Furthermore, truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (DCM), or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3/231, 1%, P=9x10-14) and healthy controls (7 of 247, 3%, P=4x10-5). Among families with multiple relatives with DCM, this study also provided strong data demonstrating segregation with disease (Herman DS et al. N Eng J Med. 2012;366:619-628). However, the functional consequence of protein truncating alterations in TTN have not been well described, and this specific alteration (TTN c.73636_73640delAAGAA) has not been reported in the literature. Therefore, this variant is likely to be pathogenic; however, due to the uncertainty of the functional and clinical consequences, its significance remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642701	SCV000764388	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys27114Glnfs*9) 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 present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 263802). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001843949	SCV002103199	likely pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing	PM2_supporting, PS4_moderate, PVS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486796	SCV004240125	likely pathogenic	Cardiomyopathy	2023-01-31	criteria provided, single submitter	clinical testing
Lildballe Lab, Aarhus University Hospital	RCV004772888	SCV005200599	likely pathogenic	Primary dilated cardiomyopathy	2024-03-01	criteria provided, single submitter	research	PVS1(vs), PM2(sup)