Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001377775 | SCV001575197 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2022-07-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the SDHA protein (p.Gly260Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma or pheochromocytoma (PMID: 25394176, 28384794, 33397043; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 1066704). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. |
| DASA | RCV001836652 | SCV002097277 | likely pathogenic | Neurodegeneration with ataxia and late-onset optic atrophy | 2022-02-14 | criteria provided, single submitter | clinical testing | Same amino acid variant as a previously established pathogenic variant regardless of nucleotide variant (ClinVar ID: 412357 - c.778G>A;p.(Gly260Arg); PMID: 25394176, 28384794) - PS1. The c.778G>C;p.(Gly260Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1066704) - PS4_supporting. This variant is not present in population databases (gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. |
| Ambry Genetics | RCV002413906 | SCV002674715 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-09 | criteria provided, single submitter | clinical testing | The p.G260R pathogenic mutation (also known as c.778G>C), located in coding exon 7 of the SDHA gene, results from a G to C substitution at nucleotide position 778. The glycine at codon 260 is replaced by arginine, an amino acid with dissimilar properties. Another alteration at the same codon, p.G260R (c.778G>A), has been detected in individuals with pheochromocytoma, paraganglioma, or SDH-deficient renal cell carcinoma (Evenepoel L et al. Genet. Med., 2015 Aug;17:610-20; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Ambry internal data). Furthermore, a functional study demonstrated that yeast equivalent of this variant (G251R) impairs function of succinate dehydrogenase complex (Bannon AE et al. Clin. Cancer Res., 2017 Nov;23:6733-6743). Based on internal structural analysis, p.G260R is anticipated to result in a significant 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. |