ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.136C>G (p.Arg46Gly) (rs74315370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216404 SCV000277214 pathogenic Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing The p.R46G pathogenic mutation (also known as c.136C>G or c.270C>G), located in coding exon 2 of the SDHB gene, results from a C to G substitution at nucleotide position 136. The arginine at codon 46 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been reported in several unrelated individuals diagnosed with paragangliomas/pheochromocytomas (Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66; Gimenez-Rogueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). Two other alterations at the same codon, p.R46Q and p.R46L, have also been reported as germline mutations in affected individuals (Panizza E et al. Hum Mol Genet. 2013 Feb 15;22(4):804-15; Miettinen M et al. Am J Surg Pathol. 2013 Feb;37(2):234-40; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The p.R46G substitution was associated with reduced SDH activity, and impairments in location of the enzyme to mitochondria and interaction with the SDHA subunit (Kim E et al, Endocr. Relat. Cancer 2015 Jun;22(3):387-97). 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 available evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000800486 SCV000940205 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-04-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 46 of the SDHB protein (p.Arg46Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with paraganglioma-pheochromocytoma syndrome (PMID: 14500403, 19454582, 15328326, Invitae). This variant is also known as 270C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 12785). This variant has been reported to affect SDHB protein function (PMID: 25972245, 28738844). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 23175444), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013626 SCV000033873 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only

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