ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.598T>C (p.Trp200Arg) (rs1557739966)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693104 SCV000820959 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 200 of the SDHB protein (p.Trp200Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary paraganglioma-pheochromocytoma syndrome (PMID: 26273102, Heller MB et al. World J. Endocr. Surg. 2010 Sept-Dec; 2(3): 135-138). 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. Variants that disrupt the p.Trp200 amino acid residue in SDHB have been observed in affected individuals (PMID:7143317, 21173220, 22835832, 20119652). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to 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.
Ambry Genetics RCV001024760 SCV001186839 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 criteria provided, single submitter clinical testing The p.W200R variant (also known as c.598T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 598. The tryptophan at codon 200 is replaced by arginine, an amino acid with dissimilar properties. This alteration, as well as a different variant at this nucleotide position (c.598T>A) that results in the same amino acid change, have been previously observed in individuals with malignant pheochromocytoma and/or paraganglioma (Heller MB et al. World J. Endocr. Surg. 2010 Sept-Dec;2(3):135-138; Buffet A et al. Horm. Metab. Res., 2012 May;44:359-66; Ambry Internal Data). In one individual, this alteration was seen in cis with a truncating SDHB variant (p.W201*) (Buffet A et al. Horm. Metab. Res., 2012 May;44:359-66). 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 internal structural assessment, this alteration disrupts the quinone binding site of SDHB (Yankovskaya V et al. Science, 2003 Jan;299:700-4; Sun F et al. Cell, 2005 Jul;121:1043-57; Ambry Internal Data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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