ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.203G>A (p.Cys68Tyr) (rs587782904)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132547 SCV000187645 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-17 criteria provided, single submitter clinical testing The p.C68Y variant (also known as c.203G>A), located in coding exon 3 of the SDHB gene, results from a G to A substitution at nucleotide position 203. The cysteine at codon 68 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple patients with paragangliomas and pheochromocytomas (Loriot et al. J Clin Endocrinol Metab. 2012 Jun;97(6):E954-62; Burnichon N et al. Hum. Mol. Genet. 2011 Oct;20:3974-85; Bennedbæk M et al. Hered Cancer Clin Pract. 2016 Jun;14:13). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000548841 SCV000630698 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-01-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 68 of the SDHB protein (p.Cys68Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs587782904, ExAC no frequency). This variant has been reported in an individual with malignant pheochromocytoma (PMID: 19576851, 22492777, 25825477, 25394176, 23707781, 21784903), and individuals with paraganglioma (PMID: 21520333, 27279923). ClinVar contains an entry for this variant (Variation ID: 143027). A structural analysis predicts that this missense change located near the 2Fe-2S cluster may affect proper SDHB protein conformation or folding (PMID: 22904323). In addition, general 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. 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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