ClinVar Miner

Submissions for variant NM_000206.2(IL2RG):c.677G>A (p.Arg226His) (rs869320660)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431556 SCV000513279 pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The R226H variant has been published previously in association with X-linked SCID (Pepper et al., 1995; Shibata et al., 2007). 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. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that R226H destabilizes the final protein (Randles et al., 2006). Missense variants in the same residue (R226C) and in nearby residues (R222C, R224W, S225R, F227C, L230P, C231R/S/Y) have been reported in the Human Gene Mutation Database in association with X-linked SCID (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
GeneReviews RCV000210841 SCV000267135 pathogenic X-linked severe combined immunodeficiency 2016-04-14 no assertion criteria provided literature only
Invitae RCV000210841 SCV000637249 pathogenic X-linked severe combined immunodeficiency 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 226 of the IL2RG protein (p.Arg226His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals from different ethnic backgrounds affected with X-linked severe combined immunodeficiency (PMID: 22039266, 11213805, 21184155, 17598841). ClinVar contains an entry for this variant (Variation ID: 225196). Experimental studies have shown that this missense change is associated with abnormal cell surface expression or recognition patterns of immunoglobin gamma chain in patient B-cells (PMID: 9058718, 11213805). In addition, thermo-dynamic analyses using an in vitro model system have also shown that this variant has an impact on protein stability (PMID: 16760466). For these reasons, this variant has been classified as Pathogenic.

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