Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000467377 | SCV000553854 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 589 of the SDHA protein (p.Arg589Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumors and paraganglioma-pheochromocytoma syndromes (PMID: 23612575, 25720320, 28384794). ClinVar contains an entry for this variant (Variation ID: 412342). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20484225, 22955521, 25405498, 28546994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| “Giorgio Prodi” Cancer Research Center, |
RCV001799664 | SCV002026126 | likely pathogenic | Gastrointestinal stromal tumor | 2021-10-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV002402299 | SCV002713371 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-18 | criteria provided, single submitter | clinical testing | The p.R589Q variant (also known as c.1766G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1766. The arginine at codon 589 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in individuals with a history of paraganglioma/pheochromocytoma (Papathomas TG et al. Mod Pathol, 2015 Jun;28:807-21; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212), as well as an individual with a gastrointestinal stromal tumor (GIST) that showed loss of SDHA by immunohistochemistry (IHC) (Pantaleo MA et al. Eur J Hum Genet, 2014 Jan;22:32-9; Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). Based on internal structural analysis, p.R589Q disrupt the structural stability (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV003476121 | SCV004200647 | likely pathogenic | Dilated cardiomyopathy 1GG | 2023-05-17 | criteria provided, single submitter | clinical testing |