ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1765C>T (p.Arg589Trp)

gnomAD frequency: 0.00002  dbSNP: rs387906780
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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, University of Bologna RCV001799611 SCV002026133 likely pathogenic Gastrointestinal stromal tumor 2021-10-01 criteria provided, single submitter research
GeneDx 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, Kuwait Cancer Control Center 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.
CeGaT Center for Human Genetics Tuebingen 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, Inc. 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, Hangzhou Juno Genomics, Inc 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

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