Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000687867 | SCV000815458 | uncertain significance | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-11-27 | 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 210 of the SDHA protein (p.Arg210Gln). This variant is present in population databases (rs762108779, gnomAD 0.005%). This missense change has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 24694336, 28384794). ClinVar contains an entry for this variant (Variation ID: 567705). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV001025100 | SCV001187226 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-07 | criteria provided, single submitter | clinical testing | The p.R210Q variant (also known as c.629G>A), located in coding exon 6 of the SDHA gene, results from a G to A substitution at nucleotide position 629. The arginine at codon 210 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in an individual with an apparently sporadic pheochromocytoma (Welander J et al. J. Clin. Endocrinol. Metab., 2014 Jul;99:E1352-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003489807 | SCV004241855 | uncertain significance | not specified | 2023-12-05 | criteria provided, single submitter | clinical testing | Variant summary: SDHA c.629G>A (p.Arg210Gln) results in a conservative amino acid change located in the FAD-dependent oxidoreductase 2, FAD binding domain (IPR003953) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251134 control chromosomes (i.e., 8 heterozygotes; gnomAD v2.1.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629G>A has been reported in the literature in individual(s) with pheochromocytoma and paraganglioma (e.g., Welander_2014, Bausch_2017), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28384794, 24694336). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |