ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.3034C>T (p.Arg1012Ter)

dbSNP: rs397517547
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Total submissions: 4
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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 RCV000040169 SCV000063860 likely pathogenic Primary dilated cardiomyopathy 2015-05-07 criteria provided, single submitter clinical testing The p.Arg1012X variant in TTN has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 1012, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A -band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expr essed in the heart (Roberts 2015). The p.Arg1012X variant is located in the high ly expressed exon 18 in the near Z-disk band. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg1012X variant is likely pathogenic.
NeuroMeGen, Hospital Clinico Santiago de Compostela RCV000754723 SCV000882610 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-10-08 criteria provided, single submitter clinical testing
Invitae RCV001314678 SCV001505220 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-01-26 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 46899). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and left ventricular non-compaction (PMID: 24503780, 27532257, 29029073). This variant is present in population databases (rs397517547, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1012*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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).
Ambry Genetics RCV002433512 SCV002750860 uncertain significance Cardiovascular phenotype 2020-01-13 criteria provided, single submitter clinical testing The p.R966* variant (also known as c.2896C>T), located in coding exon 16 of the TTN gene, results from a C to T substitution at nucleotide position 2896. This changes the amino acid from an arginine to a stop codon within coding exon 16. This exon is located in the near 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 was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). 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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