Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000520939 | SCV000616871 | pathogenic | not provided | 2022-03-30 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect; transfection of A524V into SDHA-deficient fibroblasts failed to normalize overall respiratory chain enzyme activity or SDH activity (Parfait et al., 2000); Not observed 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: 27683074, 10746566) |
| Labcorp Genetics |
RCV000649458 | SCV000771286 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 524 of the SDHA protein (p.Ala524Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Leigh syndrome and succinate dehydrogenase (SDH) deficiency (PMID: 10746566). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8743). 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: 10746566). 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 | RCV002399314 | SCV002704077 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-12 | criteria provided, single submitter | clinical testing | The p.A524V variant (also known as c.1571C>T), located in coding exon 12 of the SDHA gene, results from a C to T substitution at nucleotide position 1571. The alanine at codon 524 is replaced by valine, an amino acid with similar properties. This alteration has been detected in trans with other pathogenic SDHA mutations in individuals with features of Leigh syndrome (Parfait B et al. Hum Genet, 2000 Feb;106:236-43; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has also been reported to result in defective SDH activity in an enzymatic assay (Parfait B et al. Hum Genet, 2000 Feb;106:236-43) and is predicted to be structurally destabilizing to the protein (Ambry internal data). 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. |
| Baylor Genetics | RCV003473061 | SCV004200579 | pathogenic | Dilated cardiomyopathy 1GG | 2023-11-27 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000009282 | SCV000029500 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1 | 2000-02-01 | no assertion criteria provided | literature only |