ClinVar Miner

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

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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 RCV000166478 SCV000217276 pathogenic Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing The p.R242C pathogenic mutation (also known as c.724C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 724. The arginine at codon 242 is replaced by cysteine, an amino acid with highly dissimilar properties. <span style="background-color:initial">This alteration has been identified in numerous individuals with sporadic and familial paragangliomas/pheochromocytomas (Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78(6):898-906; <span style="background-color:initial">Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Badenhop RF et al. J. Med. Genet. 2004 Jul;41(7):e99; Schiavi F et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:190-7; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394<span style="background-color:initial">). A functional study utilizing a yeast growth assay classified this alteration as a "mildly impaired mutation" after finding that analogous yeast p.R242C mutants were able to partially rescue oxidative cell growth but had significantly decreased SDH enzyme activity (<span style="background-color:initial">Panizza E et al. Hum. Mol. Genet. 2013 Feb; 22(4):804-15)<span style="background-color:initial">. <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000461517 SCV000554036 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-04 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092589 SCV001249150 pathogenic not provided 2016-10-01 criteria provided, single submitter clinical testing

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