ClinVar Genomic variation as it relates to human health
NM_000206.3(IL2RG):c.854G>A (p.Arg285Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000206.3(IL2RG):c.854G>A (p.Arg285Gln)
Variation ID: 10026 Accession: VCV000010026.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq13.1 X: 71108599 (GRCh38) [ NCBI UCSC ] X: 70328449 (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 Apr 4, 2013 Feb 14, 2024 Oct 13, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000206.3:c.854G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000197.1:p.Arg285Gln missense NC_000023.11:g.71108599C>T NC_000023.10:g.70328449C>T NG_009088.1:g.7955G>A NG_021141.1:g.3190G>A LRG_150:g.7955G>A LRG_150t1:c.[854G>A] P31785:p.Arg285Gln - Protein change
- Other names
- R285Q
- Canonical SPDI
- NC_000023.11:71108598:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
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 | ||
---|---|---|---|---|---|---|
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 |
404 | 583 |
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. |
---|---|---|---|---|
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000010709.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 30, 2023 | RCV003231098.1 |
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
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked severe combined immunodeficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001210090.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 285 of the IL2RG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 285 of the IL2RG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IL2RG protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with X-linked severe combined immunodeficiency (PMID: 7557965, 9058718, 21184155, 22039266). This variant is also known as c.868G>A (p.R285Q). ClinVar contains an entry for this variant (Variation ID: 10026). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked severe combined immunodeficiency
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072941.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.R285Q in IL2RG (NM_000206.3) has been previusly reported in affected individuals (Lee PP et al; Jones AM et al). It falls at … (more)
The missense variant p.R285Q in IL2RG (NM_000206.3) has been previusly reported in affected individuals (Lee PP et al; Jones AM et al). It falls at the last nucleotide of exon 6 of the IL2RG coding sequence, which is part of the consensus splice site for this exon. Splicing predictions predict a damaging effect though the same has not been proved by functional studies. The variant is submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes. The p.R285Q variant is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Osteomyelitis (present) , Decreased proportion of immature B cells (present) , Severe combined immunodeficiency disease (present)
|
|
Pathogenic
(May 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003930243.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
RNA studies from a male with this variant demonstrate aberrant splicing with skipping of exon 6 (Kanai et al., 1999); Not observed at significant frequency … (more)
RNA studies from a male with this variant demonstrate aberrant splicing with skipping of exon 6 (Kanai et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32993535, 35874699, 9150740, 7557965, 10071190, 10444186, 31031743, 11129345, 33628209, 21184155) (less)
|
|
Pathogenic
(May 01, 1997)
|
no assertion criteria provided
Method: literature only
|
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030935.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with T-, B+ X-linked SCID (300400), Clark et al. (1995) identified a 2943G-A transition in the IL2RG gene, resulting in an arg285-to-gln … (more)
In a patient with T-, B+ X-linked SCID (300400), Clark et al. (1995) identified a 2943G-A transition in the IL2RG gene, resulting in an arg285-to-gln (R285Q) substitution. Jones et al. (1997) noted that X-linked SCID is characterized by the absence, or very low numbers, of T cells, with normal or even high numbers of B cells. However, in a boy with SCID who had very low numbers of both B cells and T cells, Jones et al. (1997) identified the R285Q mutation. The patient's mother and a maternal aunt were both found to have unilateral X inactivation in their T cells. Jones et al. (1997) stated that in about one-third of the cases of typical SCIDX1, there is no previous family history. In these families, the suspicion of SCIDX1 is raised by the phenotype and may be confirmed by X inactivation in T cells and/or by mutation analysis. The authors cautioned that the unexpected finding of low B cells may mistakenly suggest an autosomal form of SCID. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo. | Recher M | Blood | 2011 | PMID: 22039266 |
Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children. | Lee PP | Journal of clinical immunology | 2011 | PMID: 21184155 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
B-cell-negative severe combined immunodeficiency associated with a common gamma chain mutation. | Jones AM | Human genetics | 1997 | PMID: 9150740 |
Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. | Puck JM | Blood | 1997 | PMID: 9058718 |
Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2R gamma chain gene by single-strand conformation polymorphism analysis. | Clark PA | Human genetics | 1995 | PMID: 7557965 |
Text-mined citations for rs111033617 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.