Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002526110 | SCV000637670 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-03-08 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 184 of the TRDN protein (p.Ala184Ser). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 463678). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Gene |
RCV001555515 | SCV001776951 | uncertain significance | not provided | 2021-09-30 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Located at the last nucleotide of exon 6 at a position that is conserved across species and in silico splicing algorithms predict this variant damages or destroys the natural splice donor site of intron 6, which may affect normal gene splicing; however, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined; Reported as a variant of uncertain significance by another clinical laboratory in ClinVar (ClinVar Variant ID#463678; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918) |
| Ambry Genetics | RCV002350257 | SCV002648669 | uncertain significance | Cardiovascular phenotype | 2023-09-29 | criteria provided, single submitter | clinical testing | The p.A184S variant (also known as c.550G>T), located in coding exon 6 of the TRDN gene, results from a G to T substitution at nucleotide position 550. The alanine at codon 184 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. The nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002483410 | SCV002792266 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1; Catecholaminergic polymorphic ventricular tachycardia 5 | 2021-10-19 | criteria provided, single submitter | clinical testing |