NM_000448.3(RAG1):c.2006A>G (p.Glu669Gly) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 22, 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:: RCV003764744.2

Allele description [Variation Report for NM_000448.3(RAG1):c.2006A>G (p.Glu669Gly)]

NM_000448.3(RAG1):c.2006A>G (p.Glu669Gly)

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.2006A>G (p.Glu669Gly)

HGVS:

NC_000011.10:g.36575310A>G
NG_007528.1:g.12298A>G
NM_000448.3:c.2006A>GMANE SELECT
NM_001377277.1:c.2006A>G
NM_001377278.1:c.2006A>G
NM_001377279.1:c.2006A>G
NM_001377280.1:c.2006A>G
NP_000439.1:p.Glu669Gly
NP_000439.2:p.Glu669Gly
NP_001364206.1:p.Glu669Gly
NP_001364207.1:p.Glu669Gly
NP_001364208.1:p.Glu669Gly
NP_001364209.1:p.Glu669Gly
LRG_98t1:c.2006A>G
LRG_98:g.12298A>G
LRG_98p1:p.Glu669Gly
NC_000011.9:g.36596860A>G
NM_000448.2:c.2006A>G
P15918:p.Glu669Gly

Protein change:

E669G

Links:

UniProtKB: P15918#VAR_025983; UniProtKB/Swiss-Prot: VAR_025983; dbSNP: rs199474689

NCBI 1000 Genomes Browser:

rs199474689

Molecular consequence:

NM_000448.3:c.2006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.2006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.2006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.2006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.2006A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined immunodeficiency with skin granulomas
Synonyms:: Combined cellular and humoral immune defects with 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; Severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; See all synonyms [MedGen]
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
SCV004570842	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11133745, 24144642, 26476733, 28747913, 32655540, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004570842

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (6)
[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

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004570842.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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 sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 669 of the RAG1 protein (p.Glu669Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11133745, 24144642). ClinVar contains an entry for this variant (Variation ID: 68688). 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 not expected to disrupt RAG1 protein function. This variant disrupts the p.Glu669 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24144642, 26476733, 28747913, 32655540). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#	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: Sep 29, 2024

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