Submissions for variant NM_001267550.2(TTN):c.44400del (p.Lys14801fs)

dbSNP: rs727503628

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152353	SCV000201265	uncertain significance	not specified	2014-07-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Lys12233fs variant in TTN has not been previously reported in individuals with cardiomyopat hy. Data from large studies is insufficient to assess its frequency in the gener al population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 12233 and leads to a premat ure termination codon 3 amino acids downstream. Frameshift and other truncating variants in TTN are strongly associated with DCM, particularly if they are locat ed in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band, where the Lys12233fs variant is located, occur a t a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not rule out that this variant has a role in disease. In summary, while there is some suspicion for a pathogenic role based on the severity of the predicted impact to the protein, the clinical significanc e of the Lys12233Argfs variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220664	SCV001392669	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys14801Argfs*3) 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. ClinVar contains an entry for this variant (Variation ID: 166052). 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). 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.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764903	SCV005375149	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing