ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.724C>T (p.Arg242Cys) (rs786203251)

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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 RCV000166478 SCV000217276 pathogenic Hereditary cancer-predisposing syndrome 2016-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Invitae RCV000461517 SCV000554036 pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 242 of the SDHB protein (p.Arg242Cys). 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 more than 4 unrelated individuals with hereditary paraganglioma or pheochromocytoma (PMID: 1523504, 22517554, 19802898, 17102086, 19351833). ClinVar contains an entry for this variant (Variation ID: 186827). Experimental studies in yeast (PMID: 23175444), and algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), suggest that this variant is likely to be disruptive. A different missense substitution at this codon (p.Arg242His) has been reported in multiple individuals with hereditary paraganglioma or pheochromocytoma (PMID: 19341833, 12000816, 20208144), and has been shown to be deleterious in vitro (PMID: 22835832). This further indicates that the Arg242 residue is important for SDHB protein function. For all these reasons, this variant has been classified as Pathogenic.

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