ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.557G>A (p.Cys186Tyr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377619 SCV001575000 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 186 of the SDHB protein (p.Cys186Tyr). 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 (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma (PMID: 20208144, 17848412, 31046099, Invitae). 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. This missense change is located in the 4Fe-4S iron sulfur binding domain of the SDHB protein. This variant is predicted to alter enzymatic activity by disrupting the anchoring to the 4Fe-4S cluster present within the catalytic core of SDH (PMID: 17848412). While functional studies have not been performed to directly test the effect of this variant on SDHB protein function, this suggests this variant may be causative of disease. 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.

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