ClinVar Miner

Submissions for variant NM_000206.2(IL2RG):c.670C>T (p.Arg224Trp) (rs869320658)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255579 SCV000321775 pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing The R224W pathogenic variant has been published previously in association with X-linked SCID (Puck et al., 1997; O'Marcaigh et al., 1997; Ting et al.; 1999). The R224W 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. The 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. Functional studies have shown that R224W leads to a complete absence of the IL2RG protein on B cell surfaces (Puck et al., 1997). Missense variants in nearby residues (Y219N, R222C, R226C/H, F227C) 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.
Invitae RCV000210828 SCV000948334 pathogenic X-linked severe combined immunodeficiency 2018-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 224 of the IL2RG protein (p.Arg224Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with X-linked severe combined immunodeficiency (PMID: 9058718, 9049783, 9633906, 10792291, 21184155, 28747913). This variant is also known as c.684C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 225194). 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 and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853368 SCV000996237 pathogenic Combined immunodeficiency, X-linked 2019-01-24 criteria provided, single submitter clinical testing This variant has been previously reported as a hemizygous change in patients with X-linked severe combined immunodeficiency (SCID) (PMID: 9058718, 9049783), and reported as pathogenic by a clinical laboratory in the ClinVar database. Functional studies using B-cell lines harboring this variant in the hemizygous state from patients with SCID demonstrated that while IL2RG mRNA can be detected, its protein product cannot be detected by immunofluorescence at the cell surface (PMID: 9058718). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.670C>T (p.Arg224Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.670C>T (p.Arg224Trp) variant is classified as pathogenic.
GeneReviews RCV000210828 SCV000267133 pathogenic X-linked severe combined immunodeficiency 2016-04-14 no assertion criteria provided literature only

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