ClinVar Miner

Submissions for variant NM_000397.3(CYBB):c.1609T>C (p.Cys537Arg) (rs151344454)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059248 SCV000521157 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing The C537R variant has been previously published in association with CGD (Rae et al., 1998; Kuhns et al., 2010; Jirapongsananuruk et al., 2003). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C537R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the critical NADPH-binding region that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown that C537R nearly abolishes NADPH oxidase activity (Debeurme et al., 2010). Missense variants in nearby residues (V534D, G538E; L542S) have been reported in the Human Gene Mutation Database in association with CGD (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000585928 SCV000696682 pathogenic Chronic granulomatous disease, X-linked 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The CYBB c.1609T>C (p.Cys537Arg) variant located in the NADPH binding domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. Multiple functional studies, Jirapongsananuruk_2003, de Oliveria-Junior_2012, and Desbeurme_2010 indicate that the variant has a pathogenic effect on the protein, imparticular causing no detectable NADPH oxidase activity. The variant of interest was not observed in 86762 control chromosomes (ExAC) and multiple publications have cited the variant in affected individuals. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000585928 SCV000950724 pathogenic Chronic granulomatous disease, X-linked 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 537 of the CYBB protein (p.Cys537Arg). 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 X-linked chronic granulomatous disease (PMID: 22540226, 28168067, 12589359, 9585602). This variant is also referred to as c.1621T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 68386). This variant has been reported to affect CYBB protein function (PMID: 20724480). For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059248 SCV000090777 not provided not provided no assertion provided not provided

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