ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.2393_2394del (p.Thr798fs)

dbSNP: rs1060500528
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000459867 SCV000542892 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-08-23 criteria provided, single submitter clinical testing This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). ClinVar contains an entry for this variant (Variation ID: 405012). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr798Asnfs*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. 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.
Eurofins Ntd Llc (ga) RCV000595019 SCV000702571 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446777 SCV002736503 uncertain significance Cardiovascular phenotype 2023-10-20 criteria provided, single submitter clinical testing The c.2255_2256delCA variant, located in coding exon 13 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 2255 to 2256, causing a translational frameshift with a predicted alternate stop codon (p.T752Nfs*9). This exon is located in the Z-disk region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 99%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Schafer S et al. Nat. Genet., 2017 01;49:46-53). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017624 SCV004847619 likely pathogenic Primary dilated cardiomyopathy 2019-02-22 criteria provided, single submitter clinical testing The p.Thr798AsnfsX9 variant in TTN has not been reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions and was absent from large population studies. It has also been reported in ClinVar (Variation ID #405012). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 798 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (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.Thr798AsnfsX9 variant is located in a highly expressed exon in the Z-disk. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000595019 SCV005408934 uncertain significance not provided 2024-05-09 criteria provided, single submitter clinical testing PM2

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