Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000649422 | SCV000771250 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 447 of the SDHA protein (p.His447Arg). This variant is present in population databases (rs779151375, gnomAD 0.003%). This missense change has been observed in individuals with paraganglioma and GIST (PMID: 23797725, 27011036, 28384794; Invitae). ClinVar contains an entry for this variant (Variation ID: 539657). 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 expected to disrupt SDHA protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000770776 | SCV000902254 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-07 | criteria provided, single submitter | clinical testing | The p.H447R pathogenic mutation (also known as c.1340A>G), located in coding exon 10 of the SDHA gene, results from an A to G substitution at nucleotide position 1340. The histidine at codon 447 is replaced by arginine, an amino acid with highly similar properties. This mutation has been detected in multiple individuals with a paraganglioma or gastrointestinal stromal tumor (Mason EF et al. Am. J. Surg. Pathol., 2013 Oct;37:1612-8; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Ambry internal data). Tumors in two of the individuals showed loss of SDHA and SDHB, as well as a somatic pathogenic SDHA mutation (Mason EF et al. Am. J. Surg. Pathol., 2013 Oct;37:1612-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Gene |
RCV001552485 | SCV001773180 | uncertain significance | not provided | 2023-11-09 | criteria provided, single submitter | clinical testing | Not observed at significant frequency 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: 27011036, 28384794, 29978154, 23797725, 32741965, 36980917) |
| Baylor Genetics | RCV003472043 | SCV004202393 | uncertain significance | Dilated cardiomyopathy 1GG | 2023-10-10 | criteria provided, single submitter | clinical testing |