VCV002138599.2 - ClinVar

NM_000206.3(IL2RG):c.964C>T (p.Gln322Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

1 condition

Reviewed by expert panel

Pathogenic

Jun 2024 by ClinGen Severe… FDA Recognized Database

for X-linked severe combined immunodeficiency

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000206.3(IL2RG):c.964C>T (p.Gln322Ter)

Variation ID: 2138599 Accession: VCV002138599.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71107882 (GRCh38) [ NCBI UCSC ] X: 70327732 (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	Feb 8, 2023	Oct 26, 2024	Jun 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000206.3:c.964C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000197.1:p.Gln322Ter	nonsense
NC_000023.11:g.71107882G>A
NC_000023.10:g.70327732G>A
NG_009088.1:g.8672C>T
NG_021141.1:g.3907C>T
LRG_150:g.8672C>T
LRG_150t1:c.964C>T	LRG_150p1:p.Gln322Ter

... more HGVS ... less HGVS

Protein change

Q322*

Other names

NM_000206.3(IL2RG):c.964C>T
p.Gln322Ter

Canonical SPDI

NC_000023.11:71107881:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

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	410	594

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.
X-linked severe combined immunodeficiency	Pathogenic (2)	reviewed by expert panel	Jun 13, 2024	RCV003050620.4

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.	More information 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.
Pathogenic (Jun 13, 2024)	reviewed by expert panel (ClinGen SCID ACMG Specifications IL2RG V1.0.0) Method: curation	X-linked severe combined immunodeficiency (X-linked inheritance) Affected status: unknown Allele origin: germline	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV005375414.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c003ade5-11b1-4cf6-b78a-d11ecc369f9b Comment: The c.964C>T (p.Gln322Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, … (more) The c.964C>T (p.Gln322Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, as it is located in a critical region for protein function, PVS1 is still applied at default strength (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts); The total is 1 point, PP4 is met (PMIDs: 33628209 and 9058718). 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: PVS1, PM2_Supporting, and PP4 (VCEP specifications version 1). (less)
Pathogenic (Apr 22, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	X-linked severe combined immunodeficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003445165.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28747913‚ 30622570‚ 30778380‚ 31799703‚ 32499645‚ 9058718‚ 33628209 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IL2RG protein in which other variant(s) (p.Arg328) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IL2RG protein in which other variant(s) (p.Arg328) have been determined to be pathogenic (PMID: 28747913, 30622570, 30778380, 31799703, 32499645). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 9058718, 33628209). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln322*) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the IL2RG protein. (less)

Comment:

The c.964C>T (p.Gln322Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, as it is located in a critical region for protein function, PVS1 is still applied at default strength (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts); The total is 1 point, PP4 is met (PMIDs: 33628209 and 9058718). 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: PVS1, PM2_Supporting, and PP4 (VCEP specifications version 1).

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IL2RG protein in which other variant(s) (p.Arg328*) have been determined to be pathogenic (PMID: 28747913, 30622570, 30778380, 31799703, 32499645). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 9058718, 33628209). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln322*) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the IL2RG protein.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.	Vignesh P	Frontiers in immunology	2021	PMID: 33628209
Whole-genome sequencing of a sporadic primary immunodeficiency cohort.	Thaventhiran JED	Nature	2020	PMID: 32499645
The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.	Arcas-García A	Clinical and experimental immunology	2020	PMID: 31799703
Epstein-Barr Virus-Associated γδ T-Cell Lymphoproliferative Disorder Associated With Hypomorphic IL2RG Mutation.	Tanita K	Frontiers in pediatrics	2019	PMID: 30778380
IL2RG hypomorphic mutation: identification of a novel pathogenic mutation in exon 8 and a review of the literature.	Lim CK	Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology	2019	PMID: 30622570
Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency.	Luk ADW	Frontiers in immunology	2017	PMID: 28747913
Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency.	Puck JM	Blood	1997	PMID: 9058718
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c003ade5-11b1-4cf6-b78a-d11ecc369f9b	-	-	-	-

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000206.3(IL2RG):c.964C>T (p.Gln322Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...