Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001376967 | SCV001574177 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-05-19 | 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). ClinVar contains an entry for this variant (Variation ID: 466641). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). This variant is present in population databases (rs764985774, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg18658*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Ambry Genetics | RCV002438393 | SCV002749549 | likely pathogenic | Cardiovascular phenotype | 2023-06-23 | criteria provided, single submitter | clinical testing | The p.R9593* variant (also known as c.28777C>T), located in coding exon 115 of the TTN gene, results from a C to T substitution at nucleotide position 28777. This changes the amino acid from an arginine to a stop codon within coding exon 115. 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
| Laboratory for Molecular Medicine, |
RCV004017671 | SCV004847613 | likely pathogenic | Primary dilated cardiomyopathy | 2019-02-22 | criteria provided, single submitter | clinical testing | The p.Arg16090X variant in TTN has not been previously reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions but has been identified in 1/30584 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has been reported in ClinVar (Variation ID #466641). This nonsense variant leads to a premature termination codon at position 16090, 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-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Arg16090X variant is located in the A-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2. |