ClinVar Genomic variation as it relates to human health
NM_000536.4(RAG2):c.217C>T (p.Arg73Cys)
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_000536.4(RAG2):c.217C>T (p.Arg73Cys)
Variation ID: 36719 Accession: VCV000036719.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p12 11: 36593952 (GRCh38) [ NCBI UCSC ] 11: 36615502 (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 Apr 4, 2013 Feb 28, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000536.4:c.217C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000527.2:p.Arg73Cys missense NM_001243785.2:c.217C>T NP_001230714.1:p.Arg73Cys missense NM_001243786.2:c.217C>T NP_001230715.1:p.Arg73Cys missense NC_000011.10:g.36593952G>A NC_000011.9:g.36615502G>A NG_007573.1:g.9285C>T NG_033154.1:g.4460G>A LRG_99:g.9285C>T - Protein change
- R73C
- Other names
- NM_000536.4(RAG2):c.217C>T
- Canonical SPDI
- NC_000011.10:36593951:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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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RAG2 | - | - |
GRCh38 GRCh37 |
501 | 528 |
Conditions - Germline
Condition
Help
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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Pathogenic (1) |
criteria provided, single submitter
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Oct 9, 2023 | RCV001059752.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2021 | RCV001731320.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Aug 4, 2020 | RCV001831615.9 | |
Likely pathogenic (2) |
reviewed by expert panel
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Nov 14, 2023 | RCV003325303.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2023 | RCV003473152.1 |
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
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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
(Nov 14, 2023)
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reviewed by expert panel
Method: curation
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Recombinase activating gene 2 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Accession: SCV004102761.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys). The filtering … (more)
The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys). The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). PMID: 24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met). NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID: 20603253). In summary, this variant is classified as Likely Pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4, PM1_Supporting, PM3, PM5_Supporting, and PM2_Supporting. (VCEP specifications version 1). (less)
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Pathogenic
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Recombinase activating gene 2 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004031105.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
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Likely pathogenic
(Oct 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency with skin granulomas
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004200533.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency with skin granulomas
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001224396.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the RAG2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the RAG2 protein (p.Arg73Cys). This variant is present in population databases (rs193922574, gnomAD 0.01%). This missense change has been observed in individuals with severe combined immunodeficiency (SCID) (PMID: 20603253, 24481607, 26476733; Invitae). This variant is also known as c.811C>T. ClinVar contains an entry for this variant (Variation ID: 36719). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG2 protein function. This variant disrupts the p.Arg73 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been observed in individuals with RAG2-related conditions (PMID: 21131235, 26515615, 28747913), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Severe combined immunodeficiency disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053067.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2021 |
Comment:
Variant summary: RAG2 c.217C>T (p.Arg73Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: RAG2 c.217C>T (p.Arg73Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251454 control chromosomes. c.217C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (e.g. Adeli_2010, Pasic_2014, Dvorak_2014, Bai_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Aug 04, 2020)
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no assertion criteria provided
Method: clinical testing
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Omenn syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002087207.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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 |
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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 |
Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome. | Bai X | Immunologic research | 2016 | PMID: 26476733 |
Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection. | Dutmer CM | Journal of clinical immunology | 2015 | PMID: 26515615 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. | Dvorak CC | The Journal of allergy and clinical immunology | 2014 | PMID: 25109802 |
Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience. | Pasic S | Journal of clinical immunology | 2014 | PMID: 24481607 |
Analysis of mutations and recombination activity in RAG-deficient patients. | Asai E | Clinical immunology (Orlando, Fla.) | 2011 | PMID: 21131235 |
Why newborn screening for severe combined immunodeficiency is essential: a case report. | Adeli MM | Pediatrics | 2010 | PMID: 20603253 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ed88a6c9-e610-46f2-a97f-e3d4667b446b | - | - | - | - |
Text-mined citations for rs193922574 ...
HelpRecord last updated Apr 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.