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 Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification
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 stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-11-01 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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