rs111033618

Variant names:

• chrX-71109321-G-A
• rs111033618
• NM_000206.3:c.664C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-71109321-G-A
• chrX-71109321-G-C
• chrX-71109321-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Strong PM2_Supporting PP4_Moderate PS4

This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys) missense variant has been reported in several (atypical) SCID cases, including male (0.5pt) patient P1 (PMID:29948574) in whom the variant was detected by WES (1pt) and there was a family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study; 0.5pt), additionally STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells (1pt); together these are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate). There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID:29948574); P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID and an additional great uncle was also affected but not available for genotyping (5+ segregations; PP1_Strong). At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4) and this variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PS4, Pp1_Strong, PP4_Moderate and PM2_supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120885/MONDO:0010315/129

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 1.47
• Publications: 26 publications found

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.664C>T	p.Arg222Cys	missense_variant	Exon 5 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.664C>T	p.Arg222Cys	missense_variant	Exon 5 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.664C>T	p.Arg222Cys	missense_variant	Exon 5 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.664C>T		non_coding_transcript_exon_variant	Exon 5 of 12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096583 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361961

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840621

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000396 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:4 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 13, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 very strong, PM2 moderate, PP1 moderate, PP3 supporting -

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys) missense variant has been reported in several (atypical) SCID cases, including male (0.5pt) patient P1 (PMID: 29948574) in whom the variant was detected by WES (1pt) and there was a family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study; 0.5pt), additionally STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells (1pt); together these are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate). There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID: 29948574); P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID and an additional great uncle was also affected but not available for genotyping (5+ segregations; PP1_Strong). At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4) and this variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PS4, Pp1_Strong, PP4_Moderate and PM2_supporting. (VCEP specifications version 1). -

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 222 of the IL2RG protein (p.Arg222Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypomorphic or atypical X-linked severe combined immunodeficiency (PMID: 7557965, 9399950, 10794431, 16227049, 25042067, 29948574, 31965297). ClinVar contains an entry for this variant (Variation ID: 10027). 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. Experimental studies have shown that this missense change affects IL2RG function (PMID: 9399950, 25042067). For these reasons, this variant has been classified as Pathogenic. -

Mar 12, 2025

Next Generation Genetic Polyclinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Previously reported pathogenic missense variant in IL2RG (c.664C>T; p.Arg222Cys), located within the γc cytokine receptor domain. Functional studies and clinical data support its damaging impact on protein function, associated with X-linked Severe Combined Immunodeficiency (SCID). The variant is not found in population databases (PM2), and multiple lines of computational evidence and case reports support its pathogenicity (PP3, PS4, PP1, PM1, PM5, PP5). Detected in a hemizygous or homozygous state depending on zygosity. Classified as Pathogenic. Meets ACMG criteria: PM1, PM2, PM5, PP3, PS4, PP1, PP5. -

Combined immunodeficiency, X-linked Pathogenic:1

Dec 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Apr 26, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.53
MutPred		0.87		Loss of MoRF binding (P = 0.0017);.;.;
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.60
gMVP		0.86
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033618; hg19: chrX-70329171; COSMIC: COSV105003666; COSMIC: COSV105003666;