NM_000206.3(IL2RG):c.216C>A (p.Cys72Ter) AND X-linked severe combined immunodeficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 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:: RCV001899190.5

Allele description [Variation Report for NM_000206.3(IL2RG):c.216C>A (p.Cys72Ter)]

NM_000206.3(IL2RG):c.216C>A (p.Cys72Ter)

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.216C>A (p.Cys72Ter)

Other names:

NM_000206.3(IL2RG):c.216C>A; p.Cys72Ter

HGVS:

NC_000023.11:g.71110950G>T
NG_009088.1:g.5604C>A
NG_021141.1:g.839C>A
NM_000206.3:c.216C>AMANE SELECT
NP_000197.1:p.Cys72Ter
LRG_150:g.5604C>A
NC_000023.10:g.70330800G>T

Protein change:

C72*

Links:

dbSNP: rs2147750927

NCBI 1000 Genomes Browser:

rs2147750927

Molecular consequence:

NM_000206.3:c.216C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: X-linked severe combined immunodeficiency (SCIDX1)
Synonyms:: IMMUNODEFICIENCY 4; X-Linked Combined Immunodeficiency Diseases; Severe combined immunodeficiency, X-linked, T cell-negative, B cell-positive, NK cell-negative; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010315; MedGen: C1279481; Orphanet: 276; OMIM: 300400

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podocalyxin-like 2 [Mus musculus]
podocalyxin-like 2 [Mus musculus]
gi|31542457|ref|NP_795947.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002134397	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 30, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9058718, 10794430, 28492532
SCV004809092	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL2RG V1.0.0)	Likely pathogenic (Jan 31, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002134397

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 30, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004809092

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications IL2RG V1.0.0)

Likely pathogenic
(Jan 31, 2024)

germline

curation

Citation Link

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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

Citations

PubMed

Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency.

Puck JM, Pepper AE, Henthorn PS, Candotti F, Isakov J, Whitwam T, Conley ME, Fischer RE, Rosenblatt HM, Small TN, Buckley RH.

Blood. 1997 Mar 15;89(6):1968-77.

PubMed [citation]

PMID:: 9058718

Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency.

Niemela JE, Puck JM, Fischer RE, Fleisher TA, Hsu AP.

Clin Immunol. 2000 Apr;95(1 Pt 1):33-8.

PubMed [citation]

PMID:: 10794430

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002134397.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with IL2RG-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys72*) in the IL2RG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL2RG are known to be pathogenic (PMID: 9058718, 10794430).

#	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, SCV004809092.1

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

Description

c.216C>A (p.Cys72Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic 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: PM2_supporting,PVS1 (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: Sep 29, 2024

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