Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000156206 | SCV000205922 | likely pathogenic | Primary dilated cardiomyopathy | 2014-07-21 | criteria provided, single submitter | clinical testing | The Gly26368X variant in TTN has been identified by our laboratory in 1 young ad ult with DCM. It was absent from large population studies. This variant is predi cted to cause a frameshift which leads to a premature termination codon at posit ion 26368. This alteration is then predicted to lead to a truncated or absent pr otein. Frameshift and other truncating variants in TTN are strongly associated w ith DCM and the majority occur in the A-band (Herman 2012, Pugh 2014), where thi s variant is located. In summary, although additional studies are required to fu lly establish its clinical significance, the Gly26368X variant is likely pathoge nic. |
Genetic Services Laboratory, |
RCV000501735 | SCV000597685 | pathogenic | not provided | 2016-07-05 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000501735 | SCV000704296 | likely pathogenic | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000845492 | SCV000987590 | pathogenic | Primary familial dilated cardiomyopathy | criteria provided, single submitter | clinical testing | ||
Labcorp Genetics |
RCV001204749 | SCV001375969 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gly28936*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 31514951; Invitae). ClinVar contains an entry for this variant (Variation ID: 179417). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002354381 | SCV002656486 | likely pathogenic | Cardiovascular phenotype | 2024-08-22 | criteria provided, single submitter | clinical testing | The c.59604_59607delAAAG variant, located in coding exon 153 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 59604 to 59607, causing a translational frameshift with a predicted alternate stop codon (p.G19871*). 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 (reported as c.86799_86802delAAAG, p.Thr28933fs2aaX) has been detected in a dilated cardiomyopathy (DCM) cohort (Gigli M et al. J. Am. Coll. Cardiol., 2019 09;74:1480-1490). 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 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic. |
Clinical Genetics Laboratory, |
RCV000501735 | SCV005198657 | pathogenic | not provided | 2024-01-17 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004544450 | SCV004794005 | pathogenic | TTN-related disorder | 2023-11-14 | no assertion criteria provided | clinical testing | The TTN c.86799_86802delAAAG variant is predicted to result in premature protein termination (p.Gly28936*). This variant was reported in a dilated cardiomyopathy cohort (online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant has not been reported 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 95%-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 and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Herman et al. 2012. PMID: 22335739; Roberts et al. 2015. PMID: 25589632). In summary, this variant is categorized as pathogenic for TTN-related disorders. |