Submissions for variant NM_001267550.2(TTN):c.66685del (p.Gln22229fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV004536719	SCV004114196	likely pathogenic	TTN-related disorder	2022-10-01	criteria provided, single submitter	clinical testing	The TTN c.66685delC variant is predicted to result in a frameshift and premature protein termination (p.Gln22229Asnfs*28). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the A-band region of the protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 88-100%); however, this analysis in muscle tissue was not performed (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). Taken together, this variant is interpreted as likely pathogenic. Of note, TTN truncating variants show incomplete and age-dependent penetrance in regards to autosomal dominant dilated cardiomyopathy. ACMG has recommended the reporting of TTN truncating variants in highly expressed exons due to the significant risk of cardiomyopathy (see ACMG statement in Miller et al. 2021. PubMed ID: 34012068).