NM_000206.3(IL2RG):c.1061A>G (p.His354Arg) AND X-linked severe combined immunodeficiency

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Jan 26, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001563869.10

Allele description [Variation Report for NM_000206.3(IL2RG):c.1061A>G (p.His354Arg)]

NM_000206.3(IL2RG):c.1061A>G (p.His354Arg)

Gene:

IL2RG:interleukin 2 receptor subunit gamma [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000206.3(IL2RG):c.1061A>G (p.His354Arg)

Other names:

NM_000206.3(IL2RG):c.1061A>G; p.His354Arg

HGVS:

NC_000023.11:g.71107785T>C
NG_009088.1:g.8769A>G
NG_021141.1:g.4004A>G
NM_000206.3:c.1061A>GMANE SELECT
NP_000197.1:p.His354Arg
LRG_150:g.8769A>G
NC_000023.10:g.70327635T>C

Protein change:

H354R

Links:

dbSNP: rs771221019

Molecular consequence:

NM_000206.3:c.1061A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked severe combined immunodeficiency (SCIDX1)
Synonyms:: IMMUNODEFICIENCY 4; SCID, X-LINKED; SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-NEGATIVE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010315; MedGen: C6022468; Orphanet: 276; OMIM: 300400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001786916	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002942607	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Aug 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242248	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL2RG V1.0.0)	Likely benign (Jan 26, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001786916

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 14, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002942607

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Aug 18, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004242248

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications IL2RG V1.0.0)

Likely benign
(Jan 26, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Genome-Nilou Lab, SCV001786916.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002942607.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004242248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000206.3(IL2RG):c.1061A>G is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 354 (p.His354Arg). The filtering allele frequency (the upper threshold of the 95% CI of 7/30447) of the c.1061A>G variant in IL2RG is 0.0001216 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124 ) for PM2_Supporting. However, 4 hemizygotes were reported (PM2 not met).The variant is observed in 4 hemizygotes in gnomAD v4 (BS2_Strong). To our knowledge, this variant has not been reported in the literature in individuals affected with IL2RG related conditions or in functional studies. In summary, this variant meets the criteria to be classified as likely benign variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2 (VCEP specifications version 1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 30, 2026

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