ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162444 SCV000212794 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-05 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000539362 SCV000644763 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-11-20 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

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