ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.137G>A (p.Arg46Gln) (rs772551056)

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Total submissions: 12
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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 2018-10-18 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 alteration has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST <span style="font-family:arial,sans-serif; font-size:10pt">(Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; 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). 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. Nov;26(11):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). Two other alterations at the same codon, p.R46G and p.R46L, have also been reported as germline mutations in affected individuals (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Gimenez-Rogueplo AP et al. Cancer Res. 2003 Sep;63(17):5615-21; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Panizza E et al. Hum. Mol. Genet. 2013 Feb;22(4):804-15). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000183217 SCV000235637 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.137G>A at the cDNA level, p.Arg46Gln (R46Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in multiple individuals with paraganglioma, pheochromocytoma, and/or renal cell carcinoma (Gimenez-Roqueplo 2002, Benn 2003, Amar 2005, Burnichon 2009, van Nederveen 2009, Ricketts 2012, Fishbein 2013, Kimura 2014). Functional assays have shown that SDHB Arg46Gln reduces protein stability, drastically decreases succinate dehydrogenase activity, and activates hypoxia-inducible factors (Giminez-Roqueplo 2002, Yang 2012, Panizza 2013, Saxena 2015). SDHB Arg46Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 2Fe-2S ferredoxin-type domain (Uniprot). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000627748 SCV000287759 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 46 of the SDHB protein (p.Arg46Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs772551056, ExAC 0.001%). This variant has been reported in individuals affected 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). Experimental studies have shown that this missense change alters the first L(I)YR motif of SDHB, impairing the iron-sulfur cluster incorporation into SDHB, thus rendering the protein unstable (PMID: 22835832, 25972245, 26719882). In addition, a different missense substitution at this codon (p.Arg46Gly) is reported to be deleterious (PMID: 14500403, 15328326, 25972245). This further supports the importance of the p.Arg46 residue for SDHB protein function. 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, Partners HealthCare Personalized Medicine RCV000505310 SCV000712031 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2016-07-22 criteria provided, single submitter clinical testing The p.Arg46Gln variant in SDHB has been reported in >12 individuals with SDHB-as sociated tumors and segregated with disease in 2 affected individuals from 2 fam ilies (Gimenez-Roqueplo 2002, Benn 2003, Amar 2005, Castellano 2006, Takekoshi 2 008, Ricketts 2012, Kimura 2014). This variant has also been identified in 1/667 26 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b; dbSNP rs772551056). This frequency is low enough to be consis tent with the frequency of hereditary paragangliomas and pheochromocytomas in th e general population. In vitro functional studies provide some evidence that the p.Arg46Gln variant decreases protein stability (Saxena 2016) and activity (Kim 2016). In summary, although additional studies are required to fully establish i ts clinical significance, the p.Arg46Gln variant in SDHB is likely pathogenic.
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 Disorders 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
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505310 SCV000599484 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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