ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.50657_50660dup (p.Tyr16887Ter)

dbSNP: rs2056330918
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001056354 SCV001220795 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr16887*) 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 premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 851858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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.
Ambry Genetics RCV002445296 SCV002733059 likely pathogenic Cardiovascular phenotype 2021-02-17 criteria provided, single submitter clinical testing The c.23462_23465dupGATA variant, located in coding exon 96 of the TTN gene, results from a duplication of GATA at nucleotide positions 23462 to 23465, this changes the amino acid at position 7822 from a tyrosine to a stop codon (p.Y7822*). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (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). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV002468619 SCV002764938 likely pathogenic Reduced left ventricular ejection fraction; Noncompaction cardiomyopathy 2020-11-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002479342 SCV002792099 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-09-01 criteria provided, single submitter clinical testing

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