ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.45316_45320dup (p.Arg15108fs) (rs794729390)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184407 SCV000237032 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing The c.40393_40397dupAGCTC variant has not been published in any peer-reviewed publications to our knowledge. This variant causes a shift in reading frame starting at codon arginine 13467, changing it to an alanine, and creating a premature stop codon at position 71 of the new reading frame, denoted p.Arg13467AlafsX71. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the c.40393_40397dupAGCTC variant is located in one of the constitutive exons in the distal I-band region, and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Rahual C. Deo, 2016 ; Schafer et al., 2017). Furthermore, this variant is not observed in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000620246 SCV000735922 likely pathogenic Cardiovascular phenotype 2020-02-11 criteria provided, single submitter clinical testing The c.18121_18125dupAGCTC variant, located in coding exon 72 of the TTN gene, results from a duplication of AGCTC at nucleotide position 18121, causing a translational frameshift with a predicted alternate stop codon (p.R6043Afs*71). This exon is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). 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 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as likely pathogenic.
Invitae RCV001241598 SCV001414626 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-01-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg15108Alafs*71). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202537). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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.

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