ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.649C>G (p.Arg217Gly) (rs200245469)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480999 SCV000567351 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing The R217G variant has been reported in association with paraganglioma-pheochromocytoma syndrome(Sanso et al., 2012; van et al. 2009). The R217G substitution was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The R217G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. This substitution occurs at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Missense variants in this residue (R217G and R217L) and in nearby residues (G208E,Q214H, A215T, W218S, D224H) have been reported in the Human Gene Mutation Database inassociation with SDHB-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we consider this variant to be pathogenic.
Invitae RCV000633948 SCV000755221 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2017-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 217 of the SDHB protein (p.Arg217Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs200245469, ExAC 0.002%). This variant has been reported in an individual affected with head and neck paraganlioma (PMID: 19576851). ClinVar contains an entry for this variant (Variation ID: 419507). 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. A different missense substitution at this codon (p.Arg217Cys) has been reported in the literature in many unrelated individuals affected with hereditary pheochromocytoma (PCC) and /or paraganglioma (PGL) (PMID: 18753105, 19351833, 19454582, 19802898, 23735539). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be damaging. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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