ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.649C>T (p.Arg217Cys) (rs200245469)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162444 SCV000212794 pathogenic Hereditary cancer-predisposing syndrome 2020-04-27 criteria provided, single submitter clinical testing The p.R217C pathogenic mutation(also known as c.649C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in the germline and/or tumor of numerous individuals with paragangliomas (PGL) (Klein RD et al. Diagn Mol Pathol. 2008;17(2):94-100; Burnichon N et al. J Clin Endocrinol Metab. 2009;94(8):2817-27; Pasini B et al. J. Intern. Med. 2009 Jul; 266(1):19-42; Kimura N et al. Endocr. Relat. Cancer 2014 Jun; 21(3):L13-6; Patócs A et al. Pathol. Oncol. Res. 2016 Oct;22(4):673-9; Niemeijer ND et al. Eur. J. Endocrinol., 2017 Aug;177:115-125; Andrews KA et al. J. Med. Genet., 2018 06;55:384-394; Rijken JA et al. BJS Open, 2018 Apr;2:62-69; Richter S et al. Genet. Med., 2019 03;21:705-717; Ambry Internal Data). In one study of nearly 600 patients with head and neck PGL, p.R217C was detected in two individuals, and a second alteration at the same codon, p.R217L, was detected in another individual (Neumann HP et al. Cancer Res. 2009 Apr; 69(8):3650-6). 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.
Invitae RCV000539362 SCV000644763 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-02-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 217 of the SDHB protein (p.Arg217Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many unrelated individuals affected with hereditary pheochromocytoma (PCC) and /or paraganglioma (PGL). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 18753105, 19351833, 19454582, 19802898, 23735539, 24659481, 25047027, 26960314). ClinVar contains an entry for this variant (Variation ID: 183735). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD, and PMID: 19802898) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000984327 SCV001132525 likely pathogenic Paragangliomas 4 2017-12-13 criteria provided, single submitter curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528474 SCV001740280 pathogenic not provided no assertion criteria provided clinical testing

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