ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.574T>C (p.Cys192Arg) (rs786202732)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165688 SCV000216426 pathogenic Hereditary cancer-predisposing syndrome 2018-02-08 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; Michałowska 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). <span style="background-color:initial">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 <span style="background-color:initial">(Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). <span style="background-color:initial">Based on the available evidence, this alteration is classified as a pathogenic 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.
Invitae RCV000821774 SCV000962543 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 192 of the SDHB protein (p.Cys192Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with paragangliomas and/or pheochromocytomas many of them were classified as malignant (PMID: 27785149, 25371406, 18382370, 12000816, 22517554, 17200167). ClinVar contains an entry for this variant (Variation ID: 186150). Experimental studies have shown that this missense change increased levels of ubiquitination, which correlates with decreased stability of the SDHB protein. (PMID: 22835832). For these reasons, this variant has been classified as Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505299 SCV000599518 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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