Submissions for variant NM_003000.3(SDHB):c.600G>T (p.Trp200Cys)

gnomAD frequency: 0.00001  dbSNP: rs397516836

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162460	SCV000212817	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-01	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	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 200 of the SDHB protein (p.Trp200Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas (PMID: 17143317, 17200167, 18382370, 19184535, 19802898, 20119652, 21173220). ClinVar contains an entry for this variant (Variation ID: 183747). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (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 pheochromocytoma-paraganglioma	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.
GeneDx	RCV001577788	SCV001805236	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: results in an unstable protein and impairs binding with SDHAF1 (Yang et al., 2012; Maio et al., 2016); Not observed in large population cohorts (gnomAD); 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: 17200167, 27812541, 18840642, 19286091, 18382370, 20418362, 20119652, 28374168, 19184535, 26173966, 25371406, 21173220, 19802898, 25394176, 27011036, 23282968, 17143317, 27006389, 26749241, 29386252, 28152038, 30949620, 32741965, 33087929, 34906457, 34308366, 35668420, 34703596, 28873162, 32062700, 35060925, 35441217, 34095481, Rutkowski2022[article], 22835832)
Baylor Genetics	RCV003474841	SCV004203018	pathogenic	Gastrointestinal stromal tumor	2023-05-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001577788	SCV004230023	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with paraganglioma-pheochromocytoma syndrome. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22835832)
All of Us Research Program, National Institutes of Health	RCV000505334	SCV004821940	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 200 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant significantly reduces SDHB protein stability (PMID: 22835832). This variant has been reported in individuals affected with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, head and neck paragangliomas, and in individuals with Carney triad syndrome (PMID: 17143317, 17200167, 18382370, 19184535, 19802898, 20119652, 32741965). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000505334	SCV004847569	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-08-09	criteria provided, single submitter	clinical testing	The p.Trp200Cys variant in SDHB has been reported in over 15 individuals with paragangliomas or pheochromocytomas and segregated with disease in 1 affected relative (Timmers 2007 PMID: 17200167, Klein 2008 PMID: 18382370, Henderson 2009 PMID: 19184535, Alrashdi 2010 PMID: 20119652, Lodish 2010 PMID: 20418362, Janeway 2011 PMID: 21173220, Daniel 2016 PMID: 26173966, Andrews 2018 PMID: 29386252, Greenberg 2020 PMID: 32741965). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183747) and has been identified in 0.002% (1/41452) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). In vitro functional studies provide some evidence that this variant impacts protein stability (Yang 2012 PMID: 22835832) and computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant involving this codon (p.Trp200Arg) has been identified in individuals with hereditary paraganglioma/pheochromocytoma syndrome (Heller 2010 PMID: 26273102) and is classified as likely pathogenic in ClinVar (variation ID: 571856). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PS3_Supporting, PP3.
Myriad Genetics, Inc.	RCV001523819	SCV004933753	pathogenic	Paragangliomas 4	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17143317, 21173220, 19184535, 32741965]. Functional studies indicate this variant impacts protein function [PMID: 22835832]. This variant is expected to disrupt protein structure [Myriad internal data].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505334	SCV000599516	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research