Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825607 | SCV000966952 | likely pathogenic | Primary dilated cardiomyopathy | 2018-03-15 | criteria provided, single submitter | clinical testing | The p.Glu24416X variant in TTN has not been previously reported in individuals w ith DCM and was absent from large population studies. This nonsense variant lead s to a premature termination codon at position 24416, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-ba nd (Herman 2012, Pugh 2014) and/or are located in an exon that is highly express ed in the heart (Roberts 2015). The p.Glu24416X variant is located in A-band in the highly expressed exon 275. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Glu24416X variant is lik ely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2. |
| Ambry Genetics | RCV002345916 | SCV002647147 | likely pathogenic | Cardiovascular phenotype | 2022-06-13 | criteria provided, single submitter | clinical testing | The p.E17919* variant (also known as c.53755G>T), located in coding exon 153 of the TTN gene, results from a G to T substitution at nucleotide position 53755. This changes the amino acid from a glutamic acid to a stop codon within coding exon 153. 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 has been reported in an individual with dilated cardiomyopathy (DCM) (Rich KA et al. Mol Genet Genomic Med, 2020 10;8:e1460). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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. |