X-71109308-C-T

Position:

• chrX-71109308-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3_Supporting PP4_Moderate PM5 PM2_Supporting PS4 PM1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000206.3:c.677G>A variant in IL2RG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 226 (p.Arg226His). The variant has been observed in at least 9 probands with SCID/Ommen Syndrome (PMIDs 7668284, 9058718, 17598841, 21184155) (PS4). Among these probands, one presented with symptoms reminiscent of Omenn syndrome. The proband exhibited a T-B-NK+ lymphocyte profile. CD132 was absent in every lymphocyte subpopulation, and the NK cells isolated from the patient did not respond to IL-2 stimulation (PMID 17598841) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.677G, 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 addition, another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). 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_Strong, PM5, PP4_Moderate, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) LINK:https://erepo.genome.network/evrepo/ui/classification/CA358793/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.80

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 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.677G>A	p.Arg226His	missense_variant	5/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.677G>A	p.Arg226His	missense_variant	5/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.677G>A	p.Arg226His	missense_variant	5/8	1	NM_000206.3	ENSP00000363318	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Mar 08, 2024	The NM_000206.3:c.677G>A variant in IL2RG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 226 (p.Arg226His). The variant has been observed in at least 9 probands with SCID/Ommen Syndrome (PMIDs 7668284, 9058718, 17598841, 21184155) (PS4). Among these probands, one presented with symptoms reminiscent of Omenn syndrome. The proband exhibited a T-B-NK+ lymphocyte profile. CD132 was absent in every lymphocyte subpopulation, and the NK cells isolated from the patient did not respond to IL-2 stimulation (PMID 17598841) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.677G, 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 addition, another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). 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_Strong, PM5, PP4_Moderate, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 226 of the IL2RG protein (p.Arg226His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked severe combined immunodeficiency (PMID: 11213805, 17598841, 21184155, 22039266). ClinVar contains an entry for this variant (Variation ID: 225196). 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: 9058718, 11213805, 16760466). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2016

The R226H variant has been published previously in association with X-linked SCID (Pepper et al., 1995; Shibata et al., 2007). The 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. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that R226H destabilizes the final protein (Randles et al., 2006). Missense variants in the same residue (R226C) and in nearby residues (R222C, R224W, S225R, F227C, L230P, C231R/S/Y) 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. Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.58
MutPred		0.90		Loss of methylation at R226 (P = 0.016);.;.;
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.76

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: rs869320660; hg19: chrX-70329158; COSMIC: COSV52149638; COSMIC: COSV52149638;