ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.689G>T (p.Arg230Leu) (rs587782604)

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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 RCV000164275 SCV000214900 pathogenic Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing The p.R230L pathogenic mutation (also known as c.689G>T), located in coding exon 7 of the SDHB gene, results from a G to T substitution at nucleotide position 689. The arginine at codon 230 is replaced by leucine, an amino acid with dissimilar properties. This variant has been described in multiple unrelated individuals with extra-adrenal paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr; 69(8):3650-6; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun; 17(2):94-100; Jasperson KW et al. Fam. Cancer. 2013 Aug; Michałowska I et al. Neuroendocrinology. 2015 ; 101(4):321-30; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). In addition, two well described disease-causing mutations, p.R230H and p.R230C, have been identified at the same codon. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000473831 SCV000554032 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-07-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 230 of the SDHB protein (p.Arg230Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with paraganglioma (PMID: 18382370, 19351833, 27539324, 23934599). ClinVar contains an entry for this variant (Variation ID: 184933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Arg230 amino acid residue in SDHB has been determined to be clinically significant (PMID: 25405498, 20592014, 26259135, 16912137). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000522081 SCV000616874 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing The R230L variant in the SDHB gene has previously been reported in multiple individuals with paraganglioma and/or other features suspicious for hereditary paraganglioma-pheochromocytoma syndrome (for examples, see Klein et al., 2009; Neumann et al., 2009; Pandit et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R230L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Alternate missense variants at the same residue (R230C, R230H) have been reported in association with pheochromocytomas or functional paragangliomas, supporting the functional importance of this region of the protein (Gimenez-Roqueplo et al., 2003; Amar et al., 2005). Based on currently available evidence, we consider R230L to be pathogenic.

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