ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.600G>T (rs397516836)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162460 SCV000212817 pathogenic Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing The p.W200C pathogenic mutation (also known as c.600G>T), located in coding exon 6 of the SDHB gene, results from a G to T substitution at nucleotide position 600. The tryptophan at codon 200 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple individuals with paragangliomas (PGL), pheochromocytomas (PCC), gastrointestinal stromal tumors (GIST), other tumors associated with hereditary PGL-PCC syndrome, and has also been implicated in Carney triad (Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92(3):779-786; Lodish MB et al. Endocr. Relat. Cancer. 2010 Sep;17(3):581-8; Drucker AM and Houlden RL. Nature Clin. Pract. Endocrinol. & Metab. 2006 Dec;2(12):702-6; Henderson A et al. Fam. Cancer 2009 Jan;8(3):257-60; Alrashdi I et al. Fam Cancer 2010 Sep;9(3):443-447; Janeway KA et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(1):314-8; Andrews KA et al. J. Med. Genet. 2018 Jan; Boikos SA et al. Eur. J. Hum. Genet. 2016 Apr;24(4):569-73). In addition to the clinical data presented in the literature, functional studies demonstrated rapid and significant loss of W200C mutant SDHB protein compared to wildtype in a protein stability cell based assay (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000462889 SCV000554005 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-03-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 200 of the SDHB protein (p.Trp200Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with paragangliomas (PMID: 17200167, 17143317, 18382370, 19184535, 19802898, 20119652) or gastrointestinal stromal tumors (PMID: 21173220). A number of these cases were reported as malignant or metastatic (PMID: 17200167, 19184535, 20119652). ClinVar contains an entry for this variant (Variation ID: 183747). Experimental studies have shown that this missense change results in reduced protein stability (PMID: 22835832). For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV001523819 SCV001478181 pathogenic Paragangliomas 4 2020-12-15 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505334 SCV001519621 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2021-03-13 criteria provided, single submitter clinical testing Variant summary: SDHB c.600G>T (p.Trp200Cys) results in a non-conservative amino acid change located in the 4E-4S ferredoxin type, iron-sulfur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. c.600G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Drucker_2006, Timmers_2007, Klein_2008, Ricketts_2010, Alrashdi_2010, Greenberg_2020) and in at-least one report of an individual with gastrointestinal stromal tumor (GIST) who lacked mutations in KIT or PDGFRA (example, Janeway_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a dramatically reduced half-life reflective of increased protein degradation (example, Yang_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505334 SCV000599516 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research
GeneDx RCV001577788 SCV001805236 pathogenic not provided 2020-05-13 no assertion criteria provided clinical testing Published functional studies demonstrate a damaging effect: results in an unstable protein and impairs binding with SDHAF1 (Yang 2012, Maio 2016); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32741965, 30949620, 28152038, 29386252, 22835832, 26749241, 27006389, 17143317, 23282968, 18840642, 27011036, 25394176, 19802898, 21173220, 27812541, 25371406, 26173966, 19184535, 28374168, 20418362, 18382370, 17200167, 20119652, 19286091)

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