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 2014-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000548841 SCV000630698 uncertain significance Gastrointestinal stroma 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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