NM_000448.3(RAG1):c.1519C>T (p.Arg507Trp) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 1, 2024
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:: RCV001857789.7

Allele description [Variation Report for NM_000448.3(RAG1):c.1519C>T (p.Arg507Trp)]

NM_000448.3(RAG1):c.1519C>T (p.Arg507Trp)

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.1519C>T (p.Arg507Trp)

HGVS:

NC_000011.10:g.36574823C>T
NG_007528.1:g.11811C>T
NM_000448.3:c.1519C>TMANE SELECT
NM_001377277.1:c.1519C>T
NM_001377278.1:c.1519C>T
NM_001377279.1:c.1519C>T
NM_001377280.1:c.1519C>T
NP_000439.2:p.Arg507Trp
NP_001364206.1:p.Arg507Trp
NP_001364207.1:p.Arg507Trp
NP_001364208.1:p.Arg507Trp
NP_001364209.1:p.Arg507Trp
LRG_98t1:c.1519C>T
LRG_98:g.11811C>T
NC_000011.9:g.36596373C>T
NM_000448.2:c.1519C>T
P15918:p.Arg507Trp

Protein change:

R507W; ARG507TRP

Links:

UniProtKB: P15918#VAR_025979; OMIM: 179615.0019; dbSNP: rs104894298

Molecular consequence:

NM_000448.3:c.1519C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.1519C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.1519C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.1519C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.1519C>T - 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
SCV002291107	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 1, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11133745, 18463379, 28769923, 24290284, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002291107

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 1, 2024)

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

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, Arkwright PD, Baniyash M, Brooks EG, Conley ME, Cortes P, Duse M, Fasth A, Filipovich AM, Infante AJ, Jones A, Mazzolari E, Muller SM, Pasic S, Rechavi G, Sacco MG, Santagata S, et al.

Blood. 2001 Jan 1;97(1):81-8.

PubMed [citation]

PMID:: 11133745

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002291107.5

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 507 of the RAG1 protein (p.Arg507Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency and Omenn syndrome (PMID: 11133745, 18463379, 28769923). ClinVar contains an entry for this variant (Variation ID: 242791). 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. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). 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.

#	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: Jul 27, 2026

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