Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000554026 | SCV000651403 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 589 of the SDHA protein (p.Arg589Trp). This variant is present in population databases (rs387906780, gnomAD 0.007%). This missense change has been observed in individuals with paraganglioma or gastrointestinal stromal tumors (PMID: 20484225, 22955521, 25405498, 28546994). ClinVar contains an entry for this variant (Variation ID: 30132). 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%. Experimental studies have shown that this missense change affects SDHA function (PMID: 20484225, 21505157, 23043141). This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23612575, 28546994), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV000564186 | SCV000664568 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-11 | criteria provided, single submitter | clinical testing | The p.R589W pathogenic mutation (also known as c.1765C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1765. The arginine at codon 589 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in individuals with paraganglioma or gastrointestinal stromal tumor (Burnichon N et al. Hum. Mol. Genet., 2010 Aug;19:3011-20; Casey RT et al. Mol Genet Genomic Med, 2017 May;5:237-250; Ambry internal data). This alteration was also reported in gastrointestinal stromal tumor tissues (Pantaleo MA et al. J. Natl. Cancer Inst., 2011 Jun;103:983-7; Wagner AJ et al. Mod. Pathol., 2013 Feb;26:289-94). Several functional studies indicate that this mutation impairs succinate dehydrogenase activity and likely interferes with SDHAF2 binding which is essential for FAD insertion into SDHA (Hao HX et al. Science, 2009 Aug;325:1139-42; Burnichon N et al. Hum. Mol. Genet., 2010 Aug;19:3011-20; Kim HJ et al. J. Biol. Chem., 2012 Nov;287:40670-9; Huang S et al. Plant Signal Behav, 2013 Feb;8:e22815; Lorendeau D et al. Metab. Eng., 2017 09;43:187-197). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
“Giorgio Prodi” Cancer Research Center, |
RCV001799611 | SCV002026133 | likely pathogenic | Gastrointestinal stromal tumor | 2021-10-01 | criteria provided, single submitter | research | |
Gene |
RCV003162258 | SCV003915185 | likely pathogenic | not provided | 2022-10-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: absent SDH activity and reduced protein expression (Burnichon et al., 2010); 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: 28798025, 23043141, 21505157, 23154507, 19628817, 34014604, 22955521, 29978154, 28546994, 25405498, 20484225) |
KCCC/NGS Laboratory, |
RCV000023042 | SCV004034966 | pathogenic | Paragangliomas 5 | 2023-09-13 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs387906780, gnomAD 0.007%). This missense change has been observed in individuals with paraganglioma or gastrointestinal stromal tumors (PMID: 20484225, 22955521, 25405498, 28546994). ClinVar contains an entry for this variant (Variation ID: 30132). Experimental studies have shown that this missense change affects SDHA function (PMID: 20484225, 21505157, 23043141). This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23612575, 28546994), which suggests that this may be a clinically significant amino acid residue. Therefore, this variant has been classified as Pathogenic. |
Ce |
RCV003162258 | SCV004185249 | likely pathogenic | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | SDHA: PS3, PM1, PM5, PP3, BP1 |
Baylor Genetics | RCV003473121 | SCV004200592 | pathogenic | Dilated cardiomyopathy 1GG | 2024-02-26 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000023042 | SCV004933600 | likely pathogenic | Paragangliomas 5 | 2024-02-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27847310]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20484225, 28070496, 30949620]. |
Juno Genomics, |
RCV000023042 | SCV005417536 | likely pathogenic | Paragangliomas 5 | criteria provided, single submitter | clinical testing | PM2_Supporting+PS4_Moderate+PP4+PS3_Moderate | |
OMIM | RCV000023042 | SCV000044333 | pathogenic | Paragangliomas 5 | 2010-08-01 | no assertion criteria provided | literature only |