ClinVar Genomic variation as it relates to human health
NM_000206.3(IL2RG):c.982C>T (p.Arg328Ter)
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
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NM_000206.3(IL2RG):c.982C>T (p.Arg328Ter)
Variation ID: 418656 Accession: VCV000418656.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71107864 (GRCh38) [ NCBI UCSC ] X: 70327714 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 19, 2017 Feb 20, 2024 Jun 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000206.3:c.982C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000197.1:p.Arg328Ter nonsense NC_000023.11:g.71107864G>A NC_000023.10:g.70327714G>A NG_009088.1:g.8690C>T NG_021141.1:g.3925C>T LRG_150:g.8690C>T LRG_150t1:c.982C>T LRG_150p1:p.Arg328Ter - Protein change
- R328*
- Other names
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- Canonical SPDI
- NC_000023.11:71107863:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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IL2RG | - | - |
GRCh38 GRCh37 |
404 | 583 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2017 | RCV000483975.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2022 | RCV000586219.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2020 | RCV001090163.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Likely pathogenic
(Aug 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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X-linked severe combined immunodeficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695978.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The IL2RG c.982C>T (p.Arg328X) variant results in a premature termination codon, predicted to cause a truncated or absent IL2RG protein due to nonsense … (more)
Variant summary: The IL2RG c.982C>T (p.Arg328X) variant results in a premature termination codon, predicted to cause a truncated or absent IL2RG protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 80559 control chromosomes. This variant has been reported in two brothers with a late-onset and atypical presentation of the disease via a conference abstract. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic until more information becomes available. (less)
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Likely pathogenic
(Nov 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565878.3
First in ClinVar: Apr 27, 2017 Last updated: Dec 19, 2017 |
Comment:
The R328X nonsense variant in the IL2RG gene has been reported previously in association with immune deficiency (Chien et al., 2015; de Oliveira et al., … (more)
The R328X nonsense variant in the IL2RG gene has been reported previously in association with immune deficiency (Chien et al., 2015; de Oliveira et al., 2015; Gallo et al., 2016); however, many of these individuals were presented in abstracted case reports and detailed information is not available. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R328X results in truncation of the final 42 amino acids and is not predicted to result in nonsense-mediated decay. No downstream nonsense or missense variants have been reported in the Human Gene Mutation Database (Stenson et al., 2014). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
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Pathogenic
(Mar 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency, X-linked
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190359.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
Comment:
A hemizygous nonsense variation in exon 8 of the IL2RG gene that results in a stop codon and premature truncation of the protein at codon … (more)
A hemizygous nonsense variation in exon 8 of the IL2RG gene that results in a stop codon and premature truncation of the protein at codon 328 was detected. The observed variant c.982C>T (p.Arg328Ter) has previously been reported in a patient affected with severe combined immunodeficiency (Luk ADW. et al., 2017). The variant has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Fever (present) , Diarrhea (present) , Recurrent infections (present) , Respiratory distress (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hindu/Gujarati
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Jun 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked severe combined immunodeficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002135270.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the IL2RG protein. Other variant(s) that disrupt this region … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the IL2RG protein. Other variant(s) that disrupt this region (p.Leu329Argfs*3) have been observed in individuals with IL2RG-related conditions (PMID: 10794430). This suggests that this may be a clinically significant region of the protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this premature translational stop signal affects IL2RG function (PMID: 31799703). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 418656). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (SCID), atypical SCID, or other immunodeficiency phenotypes (PMID: 28747913, 30622570, 30778380, 31799703, 32499645). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg328*) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the IL2RG protein. (less)
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not provided
(-)
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no classification provided
Method: literature only
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X-linked severe combined immunodeficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001775478.2
First in ClinVar: Aug 14, 2021 Last updated: Oct 01, 2022 |
Comment:
Observed in 2 brothers with atypical X-SCID
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190359.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency. | Niemela JE | Clinical immunology (Orlando, Fla.) | 2000 | PMID: 10794430 |
Text-mined citations for rs1064793347 ...
HelpRecord last updated Feb 20, 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.