Submissions for variant NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)

dbSNP: rs786202732

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165688	SCV000216426	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 574. The cysteine at codon 192 is replaced by arginine, an amino acid with highly dissimilar properties.This alteration has been identified in numerous individuals with paragangliomas and pheochromocytomas (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17(2):94-100; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Michaowska I et al. Kardiochir Torakochirurgia Pol, 2016 Sep;13:276-282). In one series of functional studies, the SDHB p.C192R mutant protein was subject to premature degradation, possibly due to the increased ubiquitination levels observed in the mutant protein compared to wild type SDHB protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The Cys192 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000482399	SCV000568588	pathogenic	not provided	2016-10-04	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted SDHB c.574T>C at the cDNA level, p.Cys192Arg (C192R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been reported in numerous individuals with parangangliomas or pheochromocytomas, many of which were metastatic (Neumann 2002, Timmers 2007, Burnichon 2009, Hensen 2012, Lefebvre 2012, Michalowska 2015, Sue 2015). SDHB Cys192Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Cys192Arg occurs at a position that is conserved across species and is located in the 4Fe-4S ferredoxin-type domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821774	SCV000962543	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the SDHB protein (p.Cys192Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas many of them were classified as malignant (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). ClinVar contains an entry for this variant (Variation ID: 186150). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Myriad Genetics, Inc.	RCV003316045	SCV004018735	pathogenic	Paragangliomas 4	2023-02-08	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:33628464, 30050099, 27867439, 28503760]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV004567280	SCV005056625	pathogenic	Gastrointestinal stromal tumor	2024-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008079	SCV005631412	pathogenic	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Mitochondrial complex 2 deficiency, nuclear type 4	2024-03-06	criteria provided, single submitter	clinical testing
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505299	SCV000599518	likely pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research