ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.78489dup (p.Ile26164fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002338155 SCV002642254 likely pathogenic Cardiovascular phenotype 2018-12-31 criteria provided, single submitter clinical testing The c.51294dupC variant, located in coding exon 153 of the TTN gene, results from a duplication of C at nucleotide position 51294, causing a translational frameshift with a predicted alternate stop codon (p.I17099Hfs*11). 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%). 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 classified as likely pathogenic.

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