ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.2137C>T (p.Arg713Ter)

dbSNP: rs727505277
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156806 SCV000206527 uncertain significance not specified 2014-09-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg713X var iant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This nonsense variant leads to a p remature termination codon at position 713, which is predicted to lead to a trun cated or absent protein. Nonsense and other truncating variants in TTN are stron gly associated with DCM; however, the majority of such variants are located in t he exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), while this variant occurs in the Z-disc. In summary, while there is some suspic ion for a pathogenic role, the clinical significance of the Arg713X variant is u ncertain.
Invitae RCV001039267 SCV001202790 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-10-05 criteria provided, single submitter clinical testing 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. 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: 180003). This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 25163546, 30365001). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg713*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Baylor Genetics RCV001331619 SCV001523701 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2J 2019-11-08 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics RCV002415679 SCV002720066 uncertain significance Cardiovascular phenotype 2020-07-22 criteria provided, single submitter clinical testing The p.R667* variant (also known as c.1999C>T), located in coding exon 12 of the TTN gene, results from a C to T substitution at nucleotide position 1999. This changes the amino acid from an arginine to a stop codon within coding exon 12. 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 100%). This variant was detected in a dilated cardiomyopathy cohort; however, details were limited (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). 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.
Baylor Genetics RCV003152593 SCV003841207 uncertain significance Dilated cardiomyopathy 1G 2023-03-20 criteria provided, single submitter clinical testing

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