Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786243 | SCV000924987 | likely pathogenic | not provided | 2016-05-17 | no assertion criteria provided | provider interpretation | This variant type (frameshift) has been associated with DCM in this gene and is located in the A-band. We have seen the variant in 1 unrelated case of DCM with 2 affected family members carrying the variant. Testing was done at GeneDx. We consider this variant to be likely pathogenic, with the caveat that it may not be the sole determinant of risk. TTN nonsense variants: With >300 exons and >34,000 amino acids, TTN has the largest coding sequence in the genome. The majority of the general population will have at least 1 rare (defined as a minor allele frequency <0.5%) missense or truncating variant in this gene. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with dilated cardiomyopathy (DCM). Roberts et al (2015) observed truncating TTN variants in 13% of unselected DCM cases and 22% of end-stage DCM patients. However, to date there has been no published pedigree with a LOD score over 3.0. Truncating TTN variants are also observed in 1-3% of individuals unselected for DCM, suggesting that not all truncating TTN variants are disease-causing. In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease in affected families. Thus, while the findings of Herman et al (2012) and Roberts et al (2015) provide strong evidence that truncating TTN variants contribute to DCM, not all truncating variants appear to be disease causing, so each individual variant must be carefully examined. Herman et al (2012) reported that TTN truncating variants found in subjects with DCM (as opposed to those found in subjects without the disease) were non-randomly distributed within titin: they were overrepresented in the A-band region. Roberts et al (2015) then discovered that truncating variants found in DCM patients are more likely to be in the A band, more likely to be closer to the C terminus (though not in the M band at the very C terminus) and more likely to be in exons frequently included in dominant cardiac transcripts. In contrast, they observed that truncating variants in individuals not selected for DCM were usually in exons that are rarely transcribed in the heart. Twelve individuals in the Framingham Heart Study had a truncating TTN variant with a location suggestive of pathogenicity, but only 2 of them had signs of DCM on echo and none had overt heart failure. Taken together, this data suggests that TTN truncating variants contribute to the development of DCM, but the lack of segregation of some truncating variants with disease in families with DCM and the frequent occurrence of truncating variants in control populations makes determination of variant pathogenicity in individual cases challenging. p.Gly23041ValfsX22 TTN variant The variant appears to be novel. Review of cardiodb.org, which houses TTN transcript annotations, was performed (as of 5/17/2016). Please note that the NM_001256850.1 transcript used by GeneDx is the principal cardiac long isoform transcript, corresponding to the N2BA transcript on the cardiodb.org website. It is otherwise listed on cardiodb.org as exon 327; however, the exon 276 nomenclature will be used here for consistency. The variant is located in in the A-band and the PSI (proportion of transcripts that incorporate each exon) for exon 276 is 100%. While this variant is novel, titin truncating variants have been reported affecting the same exon in a number of studies: Felkin et al., 2016 reported TTN truncating variants in 10/70 patients with LVAD-supported, end-stage non-ischemic DCM. Four of these 10 variants were in exon 276. Fatkin et al., 2016 reported TTN truncating variants in 10/82 pediatric patients; 4 of these 10 variants were also in exon 276. Roberts et al., 2015 reported 30 truncating variants in exon 276 in their study of 5267 individuals. 27 of these patients were from DCM cohorts, another 3 were from unselected Framingham and Jackson cohorts; no truncating variants in exon 276 were seen in the two control cohorts. Pugh et al., 2014 reported TTN truncating variants in 23 / 766 patients referred to LMM for clinical genetic testing. 3 of these 23 variants were located in exon 276. Van Spaendonck-Zwarts et al., 2014 reported TTN truncating variants in 7 of 18 families with peripartum and dilated cardiomyopathy. 4 of these were in exon 276. Herman, et al., 2012 reported TTN truncating variants in 72 of a cohort6 of 312 subjects with DCM, 231 with HCM, and 249 controls. Variants in exon 276 were seen in 14 patients with DCM and 1 control. |