Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000689287 | SCV000816929 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2024-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 585 of the SDHA protein (p.Arg585Trp). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 21752896, 22517557, 23666964, 25720320, 28500238, 28546994, 29177515, 30050099; internal data). ClinVar contains an entry for this variant (Variation ID: 568815). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV004026321 | SCV004933648 | likely pathogenic | Paragangliomas 5 | 2024-02-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28546994, 21752896, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Ambry Genetics | RCV004026322 | SCV005021838 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-10 | criteria provided, single submitter | clinical testing | The c.1752_1753delACinsGT pathogenic mutation (also known as p.R585W), located in coding exon 13 of the SDHA gene, results from an in-frame deletion of AC and insertion of GT at nucleotide positions 1752 to 1753. This results in the substitution of the arginine residue for a tryptophan residue at codon 585, an amino acid with dissimilar properties. The p.R585W mutation has been identified in multiple individuals with paraganglioma, pheochromocytoma or gastrointestinal stromal tumor (Korpershoek E et al. J. Clin. Endocrinol. Metab. 2011 Sep;96:E1472-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8; Casey RT et al. Mol. Genet. Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer 2017 Jul;24:L43-L49; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 Feb;103:438-445; Richter S et al. Genet Med, 2019 03;21:705-717). Another alteration at the same codon, p.R585Q (c.1754G>A), has been detected in multiple individuals with paraganglioma or pheochromocytoma (Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56; Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). Based on internal structural analysis, p.R585W is anticipated to result in a decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |