Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825638 | SCV000967002 | likely pathogenic | Primary dilated cardiomyopathy | 2018-07-13 | criteria provided, single submitter | clinical testing | The p.Arg24941X variant in TTN has not been previously reported in individuals w ith DCM and was absent from large population studies. This variant has been repo rted in ClinVar (Variation ID 500011). This nonsense variant leads to a prematur e termination codon at position 24941, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly a ssociated with DCM if they impact the exons encoding for the A-band (Herman 2012 , Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Arg24941X variant is located in A-band in the highly expr essed exon 275. In summary, although additional studies are required to fully es tablish its clinical significance, the p.Arg24941X variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2. |
| Ambry Genetics | RCV002345917 | SCV002649387 | likely pathogenic | Cardiovascular phenotype | 2020-07-27 | criteria provided, single submitter | clinical testing | The p.R18444* variant (also known as c.55330C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 55330. This changes the amino acid from an arginine 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 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. |
| Fulgent Genetics, |
RCV002495191 | SCV002803644 | 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 | 2021-10-09 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002538222 | SCV002958444 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-06-05 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg27509*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). 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). ClinVar contains an entry for this variant (Variation ID: 667023). This premature translational stop signal has been observed in individual(s) with left ventricular non-compaction, dilated cardiomyopathy (PMID: 33500567, 35629941). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226400 | SCV003923279 | likely pathogenic | Cardiomyopathy | 2023-03-13 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.74821C>T (p.Arg24941X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248840 control chromosomes (gnomAD). c.74821C>T has been reported in the literature in an individual affected with left ventricular non-compaction (Mazzarotto_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |