rs111033618

Positions:

• chrX-71109321-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_Strong PP4_Moderate PM2_Supporting 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:5 O:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.664C>T	p.Arg222Cys	missense_variant	5/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.664C>T	p.Arg222Cys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.664C>T	p.Arg222Cys	missense_variant	5/8	1	NM_000206.3	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:3 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 13, 2021	ACMG classification criteria: PS3 supporting, PS4 very strong, PM2 moderate, PP1 moderate, PP3 supporting -
not provided, no classification provided	literature only	GeneReviews	-	- -

Combined immunodeficiency, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1997

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2017

- -

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;.;.
MutationTaster	Benign	0.94	A;A
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

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

Publications

LitVar

Other links and lift over

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