Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000692412 | SCV000820234 | uncertain significance | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-09-23 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 571301). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 312 of the SDHA protein (p.Arg312His). |
| Ambry Genetics | RCV001019215 | SCV001180544 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-25 | criteria provided, single submitter | clinical testing | The p.R312H variant (also known as c.935G>A), located in coding exon 8 of the SDHA gene, results from a G to A substitution at nucleotide position 935. The arginine at codon 312 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with a paraganglioma (Ma X et al. Front Endocrinol (Lausanne), 2020 Dec;11:574662; Ambry internal data). Based on internal structural analysis, R312H disrupts a key residue in the active site of SDHA (Reid GA et al. Biochim Biophys Acta, 2000 Aug;1459:310-5; Tomasiak TM et al. EcoSal Plus, 2007 Apr;2; Zhou Q et al. Protein Cell, 2011 Jul;2:531-42; Sharma P et al. Proc Natl Acad Sci U S A, 2020 Sep;117:23548-23556). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003472207 | SCV004200568 | uncertain significance | Dilated cardiomyopathy 1GG | 2023-09-19 | criteria provided, single submitter | clinical testing |