Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000184332 | SCV000236957 | pathogenic | not provided | 2014-04-21 | criteria provided, single submitter | clinical testing | c.71474_71475delTA: p.Ile23825ArgfsX10 (I23825RfsX10) in exon 276 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: AACA{TA}GAAG. Although the c.71474_71475delTA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Isoleucine 23825, changing it to an Arginine, and creating a premature stop codon at position 10 of the new reading frame, denoted p.Ile23825ArgfsX10. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.71474_71475delTA is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.71474_71475delTA in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000184332 | SCV000924988 | likely pathogenic | not provided | 2017-01-18 | no assertion criteria provided | provider interpretation | We consider this variant to be likely pathogenic. The Ile23825fs*10 variant in the TTN gene has not been described in the literature to the best of our knowledge. This variant is not present in population databases (ExAC). This variant in is located in the A-band of titin and is 100% spliced in. Variants in the same exon have been reported in multiple cohorts of patients DCM and cardiomyopathy. In summary, we consider this variant to be likely disease-causing. The variant is present in ClinVar, submitted by GeneDx, with whom this patient had testing. They have seen this variant in one patient, and is likely to be this patient. This variant has not, to our knowledge, been reported in the literature. TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls (indicating that not all such variants are disease-causing). While truncating variants in TTN have been associated with disease, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al. 2012). In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Roberts et al, 2015 performed cardiac phenotyping of 5267 affected and unaffected individuals as well as TTN DNA sequencing and RNA and protein analyses in heart tissue. They have a resource at cardiodb.org/titin that lists the relative inclusion of TTN exons in different isoforms and provides information to guide assessment of pathogenicity of specific truncation variants in the gene. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. The genomic coordinates for this variant are chr2:179434461. LRG exon number is 327, N2BA transcript is 276. It is located in the A-band, 100% spliced in in DCM cohorts and 95% spliced in in the GTEx cohort (Roberts et al. 2015) and is located in a multiple Ig-like and Fibronectin type III domains. Multiple variants in the same exon has previously been reported in various cohorts including adult, child and adolescent patients with DCM, patients with peripartum cardiomyopathy and healthy controls (Felkin et al 2016, Fatkin et al 2016, Herman et al 2012, Roberts et al 2015, Pugh et al 2014, van Spaendonck-Zwarts et al 2014). This variant is not present in the Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org/). A different variant at the same codon is present in ExAC (p.Ile23825Thr), which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, this variant is present in 1 out of 8,226 individuals of South Asian descent (MAF=0.006078%). |