Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152307 | SCV000201179 | likely pathogenic | Primary dilated cardiomyopathy | 2015-06-26 | criteria provided, single submitter | clinical testing | The p.Trp15645X variant in TTN has been identified by our laboratory in 1 Caucas ian adult with DCM. It was absent from large population studies. This nonsense v ariant leads to a premature termination codon at position 15645, which is predic ted to lead to a truncated or absent protein. Nonsense and other truncating vari ants in TTN are strongly associated with DCM if they are located in the exons en coding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon tha t is highly expressed in the heart (Roberts 2015). The p.Trp15645X variant is lo cated in A-band in the highly expressed exon 231. In summary, although additiona l studies are required to fully establish its clinical significance, the p.Trp15 645X variant is likely pathogenic. |
| Invitae | RCV001378774 | SCV001576425 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2015-11-05 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Likely Pathogenic. While this particular variant has not been reported in the literature, truncating variants in this region of TTN are likely pathogenic (PMID: 25589632). This sequence change creates a premature translational stop signal at codon 18213 (Trp18213*). It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002433665 | SCV002747529 | likely pathogenic | Cardiovascular phenotype | 2021-01-28 | criteria provided, single submitter | clinical testing | The p.W9148* variant (also known as c.27443G>A), located in coding exon 109 of the TTN gene, results from a G to A substitution at nucleotide position 27443. This changes the amino acid from a tryptophan to a stop codon within coding exon 109. 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Fulgent Genetics, |
RCV002483316 | SCV002789051 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 | 2021-08-03 | criteria provided, single submitter | clinical testing |