Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002460239 | SCV002618422 | likely pathogenic | Cardiovascular phenotype | 2021-03-30 | criteria provided, single submitter | clinical testing | The c.34660delG variant, located in coding exon 131 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 34660, causing a translational frameshift with a predicted alternate stop codon (p.V11554Lfs*9). 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 was reported in a dilated cardiomyopathy cohort as c.61855delG; p.Val20619LeufsTer9; however clinical details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. |