Submissions for variant NM_000206.3(IL2RG):c.670C>T (p.Arg224Trp)

dbSNP: rs869320658

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000210828	SCV004809097	pathogenic	X-linked severe combined immunodeficiency	2024-03-08	reviewed by expert panel	curation	The NM_000206.3:c.670C>T variant in IL2RG is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 224 (p.Arg226Trp). The variant has been observed in at least 10 male probands with SCID (PMIDs 28747913, 21184155, 10792291, 9633906, 9058718, 9049783) (PS4). Among these probands, one proband hemizygous for this variant was diagnosed with SCID and presented a T-B+NK- lymphocyte profile (PMID 9049783) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.670C, which is defined as a mutational hotspot by the ClinGen SCID VCEP (PMID 7668284) (PM1_Strong). Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes decreased surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM1_Strong, PS4, PP4_Supporting, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0)
GeneDx	RCV000255579	SCV000321775	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; variant leads to a complete absence of the IL2RG protein on B cell surfaces (Puck et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10444186, 9633906, 9049783, 10792291, 9058718, 32888943, 9399950, 34134972, 33628209)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210828	SCV000948334	pathogenic	X-linked severe combined immunodeficiency	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the IL2RG protein (p.Arg224Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked severe combined immunodeficiency (PMID: 9049783, 9058718, 9633906, 10792291, 21184155, 28747913). This variant is also known as c.684C>T. ClinVar contains an entry for this variant (Variation ID: 225194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL2RG protein function with a positive predictive value of 80%. 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000210828	SCV002053762	pathogenic	X-linked severe combined immunodeficiency		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255579	SCV003831700	likely pathogenic	not provided	2022-07-20	criteria provided, single submitter	clinical testing