Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000705227 | SCV000834215 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-12-25 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the SDHA protein (p.Arg451His). This variant is present in population databases (rs370690436, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma and pheochromocytoma (PMID: 26700204, 29177515; Invitae). ClinVar contains an entry for this variant (Variation ID: 581412). 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). For these reasons, this variant has been classified as Pathogenic. |
Sema4, |
RCV002256488 | SCV002527704 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-03 | criteria provided, single submitter | curation | |
Ambry Genetics | RCV002256488 | SCV003737776 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-12 | criteria provided, single submitter | clinical testing | The p.R451H variant (also known as c.1352G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1352. The arginine at codon 451 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Toledo RA et al. Clin Cancer Res, 2016 05;22:2301-10; Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743; van der Tuin K et al. J Clin Endocrinol Metab, 2018 02;103:438-445; Ambry internal data). In one study, the R451H variant was unable to grow on glycerol as carbon source, had decreased oxygen consumption and decreased Sdh2 protein. Computational modeling showed this variant disrupts flavin binding, succinate binding, and proton shuttle necessary for catalytic activity (Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743). 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. |
KTest Genetics, |
RCV001594402 | SCV001499973 | likely pathogenic | Dilated cardiomyopathy 1GG | no assertion criteria provided | clinical testing |