ClinVar Miner

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

dbSNP: rs1060500528
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 2020-08-25 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). Based on available evidence to date, the clinical significance of this alteration remains unclear.

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