Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000155948 | SCV000205660 | likely pathogenic | Primary dilated cardiomyopathy | 2018-01-19 | criteria provided, single submitter | clinical testing | The p.Glu30144X variant in TTN has not been previously reported in individuals w ith cardiomyopathy and was absent from large population studies. This nonsense v ariant leads to a premature termination codon at position 30144 which is predict ed to lead to a truncated or absent protein. Nonsense and other truncating varia nts in TTN are strongly associated with DCM if they impact the exons encoding fo r the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is high ly expressed in the heart (Roberts 2015). The p.Glu30144X variant is located in A-band in the highly expressed exon 301. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu30144X vari ant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2. |
| Invitae | RCV001378990 | SCV001576704 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2021-05-06 | criteria provided, single submitter | clinical testing | 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. 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). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 179162). 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.Glu32712*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Ambry Genetics | RCV002362826 | SCV002664068 | likely pathogenic | Cardiovascular phenotype | 2017-03-10 | criteria provided, single submitter | clinical testing | The p.E23647* variant (also known as c.70939G>T), located in coding exon 179 of the TTN gene, results from a G to T substitution at nucleotide position 70939. This changes the amino acid from a glutamic acid to a stop codon within coding exon 179. 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%). 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 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |