NM_000536.4(RAG2):c.1375A>C (p.Met459Leu) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 27, 2020
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:: RCV001378887.9

Allele description [Variation Report for NM_000536.4(RAG2):c.1375A>C (p.Met459Leu)]

NM_000536.4(RAG2):c.1375A>C (p.Met459Leu)

Gene:

RAG2:recombination activating 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000536.4(RAG2):c.1375A>C (p.Met459Leu)

HGVS:

NC_000011.10:g.36592794T>G
NG_007573.1:g.10443A>C
NG_033154.1:g.3302T>G
NM_000536.4:c.1375A>CMANE SELECT
NM_001243785.2:c.1375A>C
NM_001243786.2:c.1375A>C
NP_000527.2:p.Met459Leu
NP_001230714.1:p.Met459Leu
NP_001230715.1:p.Met459Leu
LRG_99:g.10443A>C
NC_000011.9:g.36614344T>G
NM_000536.3:c.1375A>C

Protein change:

M459L

Links:

dbSNP: rs1204766339

Molecular consequence:

NM_000536.4:c.1375A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243785.2:c.1375A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243786.2:c.1375A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined immunodeficiency with skin granulomas
Identifiers:: MONDO: MONDO:0009306; MedGen: C2673536; OMIM: 233650

Name:: Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Synonyms:: SCID, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; Severe combined immunodeficiency due to complete RAG1/2 deficiency
Identifiers:: MONDO: MONDO:0011086; MedGen: C1832322; Orphanet: 331206; OMIM: 601457

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001576576	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 27, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29772310, 26692406, 22841008, 26457731, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001576576

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 27, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.

Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, Burns S, Al-Herz W, Noroski L, Walter JE, Gennery AR, van der Burg M, Notarangelo LD, Lee YN.

J Allergy Clin Immunol. 2019 Feb;143(2):726-735. doi: 10.1016/j.jaci.2018.04.027. Epub 2018 Jun 18.

PubMed [citation]

PMID:: 29772310
PMCID:: PMC6295349

Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency.

Xu K, Liu H, Shi Z, Song G, Zhu X, Jiang Y, Zhou Z, Liu X.

Eur J Immunol. 2016 Apr;46(4):1011-9. doi: 10.1002/eji.201545896. Epub 2016 Jan 18.

PubMed [citation]

PMID:: 26692406

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001576576.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RAG2 protein function (PMID: 22841008, 29772310, 26692406). This variant has been observed to be homozygous or in combination with another RAG2 variant in individuals affected with Omenn syndrome, combined immunodeficiency with granulomatous disease and/or autoimmunity (CID-G/AI) and hyper-IgM syndrome (PMID: 22841008, 26457731). ClinVar contains an entry for this variant (Variation ID: 496632). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 459 of the RAG2 protein (p.Met459Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine.

#	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 12, 2026

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