ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)

gnomAD frequency: 0.00001  dbSNP: rs772551056
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162578 SCV000212994 pathogenic Hereditary cancer-predisposing syndrome 2021-12-08 criteria provided, single submitter clinical testing The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST (Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Benn DE et al. Oncogene, 2003 Mar;22:1358-64; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Timmers HJ et al. J Clin Endocrinol Metab, 2008 Dec;93:4826-32; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; McInerney-Leo AM et al. Clin Endocrinol (Oxf), 2014 Jan;80:25-33; Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Rijken JA et al. Clin. Genet. 2017 May; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394; Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Bayley JP et al. J Med Genet, 2020 02;57:96-103; Yonamine M et al. Cancers (Basel), 2021 Aug;13). This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57). 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.
GeneDx RCV000183217 SCV000235637 pathogenic not provided 2021-03-08 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18728283, 23083876, 15987702, 24659481, 28738844, 24102379, 31447099, 12364472, 26464466, 15476441, 22835832, 19454582, 12618761, 16317055, 17102082, 23512077, 14500403, 23282968, 23175444, 19522823, 18362451, 18840642, 19576851, 16314641, 26719882, 28374168, 27700540, 25972245, 28503760, 28944243, 29386252, 28152038, 29951630, 30487145, 30877234, 28490599, 30122538, 30694796, 31492822, 32741965)
Invitae RCV000627748 SCV000287759 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). 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 SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000232432 SCV000677773 likely pathogenic Paragangliomas 4 2017-02-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000505310 SCV000712031 pathogenic Hereditary pheochromocytoma-paraganglioma 2020-04-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000232432 SCV000782272 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Snyder Lab, Genetics Department, Stanford University RCV000722045 SCV000853087 likely pathogenic SDHB-related disorder 2017-01-01 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000183217 SCV000886095 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, Gimenez-Roqueplo 2003, Neumann 2004, Ricketts 2012). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 183793) and has been observed in the general population at a low overall frequency of 0.0004% (1/246124 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (p.Arg46Gly) has been observed in individuals affected with extra-adrenal pheochromocytoma and adrenal tumors and is considered pathogenic (Gimenez-Roqueplo 2003, Neumann 2004). The arginine at codon 46 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016). Based on the above information, this variant is considered pathogenic. References: Benn D et al. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene. 2003 Mar 6;22(9):1358-64. Gimenez-Roqueplo A et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. Neumann H et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012 Dec;188(6):2063-71. Saxena N et al. SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan; 108(1): djv287.
Fulgent Genetics, Fulgent Genetics RCV000763273 SCV000893917 pathogenic Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000232432 SCV000993583 pathogenic Paragangliomas 4 2018-08-09 criteria provided, single submitter research
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital RCV001530203 SCV001739500 pathogenic Pheochromocytoma 2020-02-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000183217 SCV002496465 pathogenic not provided 2022-01-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000232432 SCV004045422 pathogenic Paragangliomas 4 2023-04-24 criteria provided, single submitter clinical testing This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168].
Baylor Genetics RCV003474845 SCV004203032 pathogenic Gastrointestinal stromal tumor 2022-11-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000232432 SCV004362282 pathogenic Paragangliomas 4 2023-06-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV000505310 SCV004821943 pathogenic Hereditary pheochromocytoma-paraganglioma 2023-12-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Section on Medical Neuroendocrinolgy, National Institutes of Health RCV000505310 SCV000599484 pathogenic Hereditary pheochromocytoma-paraganglioma no assertion criteria provided research

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