ClinVar Miner

Submissions for variant NM_000206.2(IL2RG):c.676C>T (p.Arg226Cys) (rs869320659)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256109 SCV000321776 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing The R226C missense pathogenic variant in the IL2RG gene has been reported previously in association with X-linked SCID (Pepper et al., 1995; Jo et al., 2004; Alsina et al., 2013). It 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. The R226C pathogenic variant 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 in an extracellular domain region of the IL2RG protein where amino acids with similar properties to Arginine are tolerated across species; however, this residue is also hotspot codon for deleterious variants. Functional studies have shown that R226C impairs expression of the IL2RG protein (Kumaki et al., 1995). Missense variants at the same codon (R226H) and in nearby residues (R222C, R224W, F227C, L230P, C231R/Y/S) have been reported in the Human Gene Mutation Database in association with SCID (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000210834 SCV000637248 pathogenic X-linked severe combined immunodeficiency 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 226 of the IL2RG protein (p.Arg226Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). Codon 226 has been reported as a mutation hot spot (PMID: 7668284) and this variant has been observed as a de novo or germline mutation in multiple individuals affected with SCID (PMID: 23683512, 22039266, 9058718, 14966353). ClinVar contains an entry for this variant (Variation ID: 225195). This variant generates a cysteine residue in the extracellular domain of the IL2RG protein. This cysteine residue is expected to compete with natural occurring cysteines in the formation of natural disulfide bridges that provide strong spatial constraints for tertiary folding of the IL2RG protein (PMID: 2169613, 9058718). In addition, variants in the extracellular domain of the IL2RG gene that substitute or generate cysteine residues are overrepresented among patients with SCID (PMID: 8961626). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that has only been observed in affected individuals and is expected to affect protein stability and predicted to disrupt protein function. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763631 SCV000894499 pathogenic Combined immunodeficiency, X-linked; X-linked severe combined immunodeficiency 2018-10-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853350 SCV000996214 pathogenic Combined immunodeficiency, X-linked 2018-11-21 criteria provided, single submitter clinical testing The c.676C>T, p.Arg226Cys has previously been reported in the literature as pathogenic (PMID: 7668284, 23683512) and by clinical laboratories in ClinVar as associated with X-linked SCID. Missense variants at the same codon (R226H) have also been identified in patients with SCID (PMID: 7668284). Functional characterization of the variant indicate that the p.Arg226Cys substitution (referred to as p.Arg204Cys in the literature) results in the lack of cell surface expression of the IL2 receptor gamma chain (PMID: 7632950). There are no reports of the variant in the population allele frequency database, gnomAD, thus the variant is presumed rare. The variant results in a non-conservative amino acid change at a conserved residue, and in silico protein models predict a damaging effect on protein function. Based on the combined evidence, this variant is classified as pathogenic.
GeneReviews RCV000210834 SCV000267134 pathogenic X-linked severe combined immunodeficiency 2016-04-14 no assertion criteria provided literature only
Counsyl RCV000210834 SCV001132234 pathogenic X-linked severe combined immunodeficiency 2018-03-12 no assertion criteria provided clinical testing

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