ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57300_57303dup (p.Ile19102Ter)

dbSNP: rs1553659902
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000622329 SCV000740284 likely pathogenic Dilated cardiomyopathy 1G 2017-11-09 criteria provided, single submitter clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000622329 SCV000740286 likely pathogenic Dilated cardiomyopathy 1G 2017-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV005298555 SCV005957235 likely pathogenic Cardiovascular phenotype 2025-03-06 criteria provided, single submitter clinical testing The c.30105_30108dupTAGA variant, located in coding exon 121 of the TTN gene, results from a duplication of TAGA at nucleotide position 30105, causing a translational frameshift with a predicted alternate stop codon (p.I10037*). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant 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 (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; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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