NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln) AND Severe combined immunodeficiency disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003230361.1

Allele description [Variation Report for NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)]

NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)

Gene:

RAG1:recombination activating 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)

HGVS:

NC_000011.10:g.36575637G>A
NG_007528.1:g.12625G>A
NM_000448.3:c.2333G>AMANE SELECT
NM_001377277.1:c.2333G>A
NM_001377278.1:c.2333G>A
NM_001377279.1:c.2333G>A
NM_001377280.1:c.2333G>A
NP_000439.1:p.Arg778Gln
NP_000439.2:p.Arg778Gln
NP_001364206.1:p.Arg778Gln
NP_001364207.1:p.Arg778Gln
NP_001364208.1:p.Arg778Gln
NP_001364209.1:p.Arg778Gln
LRG_98t1:c.2333G>A
LRG_98:g.12625G>A
LRG_98p1:p.Arg778Gln
NC_000011.9:g.36597187G>A
NM_000448.2:c.2333G>A
P15918:p.Arg778Gln

Protein change:

R778Q; ARG778GLN

Links:

UniProtKB: P15918#VAR_045958; OMIM: 179615.0020; dbSNP: rs121918569

NCBI 1000 Genomes Browser:

rs121918569

Molecular consequence:

NM_000448.3:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.2333G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Severe combined immunodeficiency disease (SCID)
Synonyms:: Severe combined immunodeficiency; Bubble boy disease; Severe Combined Immune Deficiency
Identifiers:: MONDO: MONDO:0015974; MeSH: D016511; MedGen: C0085110; Human Phenotype Ontology: HP:0004430

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003928986	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18463379, 27609655, 24290284, 33628209 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003928986

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 28, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An immunodeficiency disease with RAG mutations and granulomas.

Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knüchel R, Göbel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T.

N Engl J Med. 2008 May 8;358(19):2030-8. doi: 10.1056/NEJMoa073966.

PubMed [citation]

PMID:: 18463379

Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium.

Kumánovics A, Lee YN, Close DW, Coonrod EM, Ujhazi B, Chen K, MacArthur DG, Krivan G, Notarangelo LD, Walter JE.

J Allergy Clin Immunol. 2017 Feb;139(2):690-692.e3. doi: 10.1016/j.jaci.2016.07.027. Epub 2016 Sep 5.

PubMed [citation]

PMID:: 27609655
PMCID:: PMC5303162

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928986.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: RAG1 c.2333G>A (p.Arg778Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251206 control chromosomes. c.2333G>A has been reported in the literature in homozygote and compound heterozygote individuals affected with Severe Combined Immunodeficiency (examples: Scheutz_2008, Kumanovics_2017, Vignesh_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal VDJ recombination activity (examples: Scheutz_2008, Lee_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27609655, 24290284, 18463379, 33628209). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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