Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000118769 | SCV000153309 | pathogenic | Tibial muscular dystrophy | 2013-12-23 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001053412 | SCV001217671 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-09-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg1683*) 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). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 130673). This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002336259 | SCV002636905 | uncertain significance | Cardiovascular phenotype | 2024-07-10 | criteria provided, single submitter | clinical testing | The p.R1637* variant (also known as c.4909C>T), located in coding exon 26 of the TTN gene, results from a C to T substitution at nucleotide position 4909. This changes the amino acid from an arginine to a stop codon within coding exon 26. This exon is located in the Z-disk/I-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. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM (Herman DS et al. N. Engl. J. Med. 2012;366:619-28; Roberts AM et al. Sci Transl Med. 2015;7:270ra6; Schafer S et al. Nat. Genet. 2017;49:46-53). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV002464117 | SCV002758976 | uncertain significance | not provided | 2022-11-22 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge |
Laboratory for Molecular Medicine, |
RCV004017402 | SCV004847984 | likely pathogenic | Primary dilated cardiomyopathy | 2019-01-25 | criteria provided, single submitter | clinical testing | The p.Arg1683X variant in TTN has not been previously reported in individuals with DCM and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1683, 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). The p.Arg1683X variant is located in a highly expressed exon near the Z-disk/I-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 autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2. |