NM_000536.4(RAG2):c.1375A>C (p.Met459Leu) AND Histiocytic medullary reticulosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 1, 2025
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:: RCV001834862.2

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:: Histiocytic medullary reticulosis
Synonyms:: SEVERE COMBINED IMMUNODEFICIENCY WITH HYPEREOSINOPHILIA; Omenn syndrome
Identifiers:: MONDO: MONDO:0011338; MedGen: C2700553; Orphanet: 39041; OMIM: 603554

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002090400	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Jun 1, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29410113, 26457731, 22841008 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002090400

Natera, Inc.

criteria provided, single submitter

(Natera Variant Classification Schema (03/2026))

Likely pathogenic
(Jun 1, 2025)

germline

clinical testing

PubMed (3)
[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

Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies.

Goda V, Malik A, Kalmar T, Maroti Z, Patel B, Ujhazi B, Csomos K, Hale JE, Chen K, Bleesing J, Palma P, Cancrini C, Comeau AM, Krivan G, Walter JE.

J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1769-1771.e2. doi: 10.1016/j.jaip.2018.01.015. Epub 2018 Feb 2. No abstract available.

PubMed [citation]

PMID:: 29410113
PMCID:: PMC6072614

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, et al.

J Clin Invest. 2015 Nov 2;125(11):4135-48. doi: 10.1172/JCI80477. Epub 2015 Oct 12. Erratum in: J Clin Invest. 2016 Nov 1;126(11):4389. doi: 10.1172/JCI91162..

PubMed [citation]

PMID:: 26457731
PMCID:: PMC4639965

See all PubMed Citations (3)

Details of each submission

From Natera, Inc., SCV002090400.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.1375A>C variant in RAG2 is a missense variant predicted to cause substitution of methionine to leucine at amino acid 459. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29410113, 26457731, 22841008). Additionally, this variant has been observed to segregate in affected family members (PMID: 22841008). Functional studies show that this variant may disrupt protein function (PMID: 22841008). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely 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 12, 2026

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