Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | 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 | RCV002536395 | SCV003737776 | likely pathogenic | Inborn genetic diseases | 2022-02-04 | criteria provided, single submitter | clinical testing | The c.1352G>A (p.R451H) alteration is located in exon 10 (coding exon 10) of the SDHA gene. This alteration results from a G to A substitution at nucleotide position 1352, causing the arginine (R) at amino acid position 451 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251174) total alleles studied. The highest observed frequency was <0.01% (1/113456) of European (non-Finnish) alleles. Three alterations at the same codon, c.1352G>A (p.R451H), c.1351C>T (p.R451C), and c.1351C>A (p.R451S), have been reported previously. The p.R451H variant has been described in individuals with paraganglioma and gastrointestinal stromal tumor (Toledo, 2016; Bannon, 2017; van der Tuin, 2018). In contrast, the p.R451C variant has been detected in two unrelated families with an apparently autosomal dominant form of complex II deficiency (Birch-Machin, 2000; Courage, 2017). The p.R451S variant has been reported to be the result of a de novo mutation or germline mosaicism in one individual with complex II deficiency (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant likely disrupts the local structure of a ligand binding site in the SDHA protein (Sun, 2005; Iverson, 2012; Inaoka, 2015). Functional studies using yeast and bacteria models showed that the p.R451H and p.R451C variants impair SDHA activity (Birch-Machin, 2000; Bannon, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| KTest Genetics, |
RCV001594402 | SCV001499973 | likely pathogenic | Dilated cardiomyopathy 1GG | no assertion criteria provided | clinical testing |