Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152492 | SCV000201639 | uncertain significance | not specified | 2014-10-10 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln2548X variant in TTN gene has not been previously reported in individuals with cardiom yopathy or in large population studies. This nonsense variant leads to a prematu re termination codon at position 2548, which is predicted to lead to a truncated or absent protein. However, variants in the I-band of the TTN gene, where this variant is located, occur at a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not eliminate the possibility that this variant has a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Gln254 8X variant is uncertain. |
| Invitae | RCV001326015 | SCV001517027 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2022-06-20 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 166307). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln2548*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Prevention |
RCV003975190 | SCV004793756 | likely pathogenic | TTN-related condition | 2024-01-16 | criteria provided, single submitter | clinical testing | The TTN c.7642C>T variant is predicted to result in premature protein termination (p.Gln2548*). This variant occurs within the I-band region of the titin protein. RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts AM et al. 2015. PubMed ID: 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 AM et al. 2015. PubMed ID: 25589632; Herman DS et al. 2012. PubMed ID: 22335739). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Of note, truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer S et al. 2017. PubMed ID: 27869827). In addition, truncating TTN variants have also been associated with autosomal recessive congenital myopathy (Ceyhan-Birsoy O et al. 2013. PubMed ID: 23975875). Therefore, the c.7642C>T (p.Gln2548*) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders. |