Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000460623 | SCV000553870 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-12-19 | 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). 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 missense change has been observed in individuals with paraganglioma or pheochromocytoma (PMID: 25394176, 28384794, 33219105, 33397043; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 412357). 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. Experimental studies have shown that this missense change affects SDHA function (PMID: 28724664). 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. |
| Ambry Genetics | RCV001026811 | SCV001189266 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-12-14 | criteria provided, single submitter | clinical testing | The p.G260R variant (also known as c.778G>A), located in coding exon 7 of the SDHA gene, results from a G to A substitution at nucleotide position 778. The glycine at codon 260 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals diagnosed with paragangliomas, pheochromocytomas and/or SDH-deficient renal cell carcinoma (Ambry internal data; Evenepoel L et al. Genet. Med., 2015 Aug;17:610-20; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Seo SH et al. Endocrinol Metab (Seoul), 2020 12;35:909-917; Kim JH et al. J Med Genet, 2022 Jan;59:56-64). 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. |
| Gene |
RCV001775823 | SCV002013943 | likely pathogenic | not provided | 2024-04-02 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect: reduced oxidative phosphorylation and decreased protein expression (PMID: 28724664); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27051561, 25394176, 28384794, 29177515, 33397043, 33219105, 28724664) |
| Revvity Omics, |
RCV001775823 | SCV002019153 | likely pathogenic | not provided | 2020-11-30 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003476124 | SCV004200631 | likely pathogenic | Dilated cardiomyopathy 1GG | 2023-06-26 | criteria provided, single submitter | clinical testing |