Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152223 | SCV000201010 | likely pathogenic | Primary dilated cardiomyopathy | 2014-06-19 | criteria provided, single submitter | clinical testing | The Ala21311fs variant in TTN has not been reported in individuals with cardiomy opathy and data from large population studies is insufficient to assess its freq uency. This variant is predicted to cause a frameshift, which alters the protein ?s amino acid sequence beginning at position 21311 and lead to a premature termi nation codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in T TN are strongly associated with DCM and the majority occur in the A-band (Herman 2012, Pugh 2014), where this variant is located. In summary, although additiona l studies are required to fully establish its clinical significance, the Ala2131 1fs variant is likely pathogenic. |
| Invitae | RCV000691893 | SCV000819691 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-04-17 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Ala23879Leufs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 165852). This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). Truncating variants in TTN have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002326872 | SCV002633195 | likely pathogenic | Cardiovascular phenotype | 2022-06-29 | criteria provided, single submitter | clinical testing | The c.44439delA variant, located in coding exon 153 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 44439, causing a translational frameshift with a predicted alternate stop codon (p.A14814Lfs*2). 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 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 dilated cardiomyopathy (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). As such, this alteration is classified as likely pathogenic. |