ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.650G>A (p.Arg217His) (rs747518441)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475294 SCV000554038 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 217 of the SDHB protein (p.Arg217His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs747518441, ExAC 0.002%). This variant has not been reported in the literature in individuals with SDHB-related disease. ClinVar contains an entry for this variant (Variation ID: 412491). 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 determined to be pathogenic (PMID: 18753105, 19351833, 19454582, 19802898, 23735539, 24659481, 25047027, 26960314). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. 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.
Mendelics RCV000708781 SCV000837729 likely pathogenic Cowden syndrome 2018-07-02 criteria provided, single submitter clinical testing

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