VCV001199323.9 - ClinVar

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

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely benign

for X-linked severe combined immunodeficiency

Classification is based on the expert panel submission

Jan 2024 by ClinGen Severe Combined Immunodeficiency Variant Curation E…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1199323 Accession: VCV001199323.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71107785 (GRCh38) [ NCBI UCSC ] X: 70327635 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 18, 2021	Feb 15, 2026	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000206.3:c.1061A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000197.1:p.His354Arg	missense
NC_000023.11:g.71107785T>C
NC_000023.10:g.70327635T>C
NG_009088.1:g.8769A>G
NG_021141.1:g.4004A>G
LRG_150:g.8769A>G

... more HGVS ... less HGVS

Protein change

H354R

Other names

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

Canonical SPDI

NC_000023.11:71107784:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA10443761 dbSNP: rs771221019 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IL2RG		-	-	GRCh38 GRCh37	511	710

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Combined immunodeficiency, X-linked	Uncertain significance (1)	criteria provided, single submitter	Jul 14, 2021	RCV001563868.3
X-linked severe combined immunodeficiency	Likely benign (3)	reviewed by expert panel	Jan 26, 2024	RCV001563869.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Jan 26, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen SCID ACMG Specifications IL2RG V1.0.0)	X-linked severe combined immunodeficiency (X-linked inheritance)	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004242248.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c507f13c-43cd-4cfe-b95f-fa1e3960702c Comment: show 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). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Uncertain significance (Jul 14, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Combined immunodeficiency, X-linked	Genome-Nilou Lab Accession: SCV001786915.2 First in ClinVar: Aug 18, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: mixed

Uncertain significance (Jul 14, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	X-linked severe combined immunodeficiency	Genome-Nilou Lab Accession: SCV001786916.2 First in ClinVar: Aug 18, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: mixed

Likely benign (Aug 18, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	X-linked severe combined immunodeficiency	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002942607.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

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).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c507f13c-43cd-4cfe-b95f-fa1e3960702c	-	-	-	-

Text-mined citations for rs771221019 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 30, 2026