NM_000536.4(RAG2):c.476G>A (p.Arg159His) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 8, 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:: RCV002040484.8

Allele description [Variation Report for NM_000536.4(RAG2):c.476G>A (p.Arg159His)]

NM_000536.4(RAG2):c.476G>A (p.Arg159His)

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.476G>A (p.Arg159His)

HGVS:

NC_000011.10:g.36593693C>T
NG_007573.1:g.9544G>A
NG_033154.1:g.4201C>T
NM_000536.4:c.476G>AMANE SELECT
NM_001243785.2:c.476G>A
NM_001243786.2:c.476G>A
NP_000527.2:p.Arg159His
NP_001230714.1:p.Arg159His
NP_001230715.1:p.Arg159His
LRG_99:g.9544G>A
NC_000011.9:g.36615243C>T

Protein change:

R159H

Links:

dbSNP: rs2133314621

Molecular consequence:

NM_000536.4:c.476G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243785.2:c.476G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243786.2:c.476G>A - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002300986	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24144642, 28747913, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002300986

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 8, 2023)

germline

clinical testing

PubMed (3)
[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

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, Schwarz K, Schulz AS, Hoenig M, Sparber-Sauer M, Gatz SA, Denzer C, Blanche S, Moshous D, Picard C, Horn BN, de Villartay JP, Cavazzana M, Debatin KM, Friedrich W, Fischer A, Cowan MJ.

Blood. 2014 Jan 9;123(2):281-9. doi: 10.1182/blood-2013-01-476432. Epub 2013 Oct 21. Erratum in: Blood. 2018 Dec 6;132(23):2527. doi: 10.1182/blood-2018-10-882217..

PubMed [citation]

PMID:: 24144642
PMCID:: PMC3953035

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency.

Luk ADW, Lee PP, Mao H, Chan KW, Chen XY, Chen TX, He JX, Kechout N, Suri D, Tao YB, Xu YB, Jiang LP, Liew WK, Jirapongsananuruk O, Daengsuwan T, Gupta A, Singh S, Rawat A, Abdul Latiff AH, Lee ACW, Shek LP, Nguyen TVA, et al.

Front Immunol. 2017;8:808. doi: 10.3389/fimmu.2017.00808.

PubMed [citation]

PMID:: 28747913
PMCID:: PMC5506088

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002300986.5

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

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 disrupts the p.Arg159 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24144642, 28747913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1508684). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 159 of the RAG2 protein (p.Arg159His).

#	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

ClinVar

Relating variation to medicine