Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002526104 | SCV000637659 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-12-03 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 59 of the TRDN protein (p.Thr59Met). This variant is present in population databases (rs397515459, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TRDN-related conditions (PMID: 30649896; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 463670). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRDN protein function with a positive predictive value of 80%. This variant disrupts the p.Thr59 amino acid residue in TRDN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22422768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002413505 | SCV002716831 | uncertain significance | Cardiovascular phenotype | 2020-10-28 | criteria provided, single submitter | clinical testing | The p.T59M variant (also known as c.176C>T), located in coding exon 2 of the TRDN gene, results from a C to T substitution at nucleotide position 176. The threonine at codon 59 is replaced by methionine, an amino acid with similar properties. This variant has been reported in one individual with a history of sudden cardiac arrest, prolonged QTc, and T-wave inversions, who also had a second TRDN splicing variant detected; however, confirmation of phase (cis or trans) information was not provided (Clemens DJ et al. Circ Genom Precis Med, 2019 02;12:e002419). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Neuberg Centre For Genomic Medicine, |
RCV004546515 | SCV005042596 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 5 | criteria provided, single submitter | clinical testing | The missense variant c.176C>Tp.Thr59Met in TRDN gene has been observed in compound heterozygous state in individuals with clinical features of TRDN-related conditions Clemens et. al., 2019. The p.Thr59Met variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.002% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic / Uncertain Significance. The amino acid change p.Thr59Met in TRDN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 59 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance VUS. |