ClinVar Genomic variation as it relates to human health
NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)
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_000448.3(RAG1):c.1331C>T (p.Ala444Val)
Variation ID: 68681 Accession: VCV000068681.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p12 11: 36574635 (GRCh38) [ NCBI UCSC ] 11: 36596185 (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 Oct 31, 2013 Apr 15, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000448.3:c.1331C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000439.2:p.Ala444Val missense NM_001377277.1:c.1331C>T NP_001364206.1:p.Ala444Val missense NM_001377278.1:c.1331C>T NP_001364207.1:p.Ala444Val missense NM_001377279.1:c.1331C>T NP_001364208.1:p.Ala444Val missense NM_001377280.1:c.1331C>T NP_001364209.1:p.Ala444Val missense NC_000011.10:g.36574635C>T NC_000011.9:g.36596185C>T NG_007528.1:g.11623C>T LRG_98:g.11623C>T LRG_98t1:c.1331C>T LRG_98p1:p.Ala444Val P15918:p.Ala444Val - Protein change
- A444V
- Other names
- NM_000448.3(RAG1):c.1331C>T
- Canonical SPDI
- NC_000011.10:36574634:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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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
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. |
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RAG1 | - | - |
GRCh38 GRCh37 |
820 | 846 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Jul 1, 2019 | RCV000059562.17 | |
Pathogenic (1) |
no assertion criteria provided
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May 1, 2022 | RCV000559478.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV001390074.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 20, 2022 | RCV002281904.2 | |
Pathogenic (1) |
reviewed by expert panel
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Nov 14, 2023 | RCV003398651.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2023 | RCV003474645.1 |
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. |
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Pathogenic
(Nov 14, 2023)
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reviewed by expert panel
Method: curation
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Recombinase activating gene 1 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Accession: SCV004102815.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID … (more)
The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199; PM1). The popmax allele frequency is 0.00003266 (1/30614 alleles) in the South Asisan population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). At least 11 patients have been reported with this variant (PMIDs: 26596586, 24290284, 23085344, 17572155, 11133745, 36596882, 29410113), including patient 11 of PMID: 26596586 whom meets diagnostic criteria for SCID with a T-B-NK+ lymphocyte subset profile which is specific to recombinase activating gene 1 deficiency (PP4). Six patients are homozygous for this variant (PMIDs: 24290284, 17572155,11133745; 1pt maximum) and five are compound heterozygous (PMIDs: 26596586, 23085344, 11133745, 36596882, 29410113), harboring this variant as well as c.256_257 (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM2_supporting, PP4, PM3_Strong, PS3_Moderate. (VCEP specifications version 1). (less)
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Pathogenic
(Jul 20, 2022)
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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: SCV002570605.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: RAG1 c.1331C>T (p.Ala444Val) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of the encoded protein sequence. Five … (more)
Variant summary: RAG1 c.1331C>T (p.Ala444Val) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of 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 1.2e-05 in 250826 control chromosomes. c.1331C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency/Atypical SCID/Omenn syndrome (example, Villa_2001, Haq_2007, Sharapova_2012, Firtina_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Lee_2014). The most pronounced variant effect results in 1.4% of normal VDJ recombination activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Combined immunodeficiency due to partial RAG1 deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004200455.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 08, 2024)
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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: SCV001591682.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 444 of the RAG1 protein (p.Ala444Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 444 of the RAG1 protein (p.Ala444Val). This variant is present in population databases (rs199474685, gnomAD 0.003%). This missense change has been observed in individuals with primary immunodeficiency (PMID: 11133745, 23085344, 24290284, 26596586; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68681). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248253.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 01, 2022)
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no assertion criteria provided
Method: clinical testing
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Affected status: yes
Allele origin:
germline
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Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573422.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091094.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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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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Mutational landscape of severe combined immunodeficiency patients from Turkey. | Firtina S | International journal of immunogenetics | 2020 | PMID: 32445296 |
Molecular Characteristics, Clinical and Immunologic Manifestations of 11 Children with Omenn Syndrome in East Slavs (Russia, Belarus, Ukraine). | Sharapova SO | Journal of clinical immunology | 2016 | PMID: 26596586 |
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. | Lee YN | The Journal of allergy and clinical immunology | 2014 | PMID: 24290284 |
Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male. | Sharapova SO | Human immunology | 2013 | PMID: 23085344 |
GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes. | Haq IJ | Clinical immunology (Orlando, Fla.) | 2007 | PMID: 17572155 |
V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. | Villa A | Blood | 2001 | PMID: 11133745 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4c48f76d-1958-49ce-9365-ac8fe43b0175 | - | - | - | - |
Text-mined citations for rs199474685 ...
HelpRecord last updated Apr 15, 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.