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NM_000448.3(RAG1):c.2005G>A (p.Glu669Lys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 18, 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:
RCV003765454.2

Allele description [Variation Report for NM_000448.3(RAG1):c.2005G>A (p.Glu669Lys)]

NM_000448.3(RAG1):c.2005G>A (p.Glu669Lys)

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.2005G>A (p.Glu669Lys)
HGVS:
  • NC_000011.10:g.36575309G>A
  • NG_007528.1:g.12297G>A
  • NM_000448.3:c.2005G>AMANE SELECT
  • NM_001377277.1:c.2005G>A
  • NM_001377278.1:c.2005G>A
  • NM_001377279.1:c.2005G>A
  • NM_001377280.1:c.2005G>A
  • NP_000439.2:p.Glu669Lys
  • NP_001364206.1:p.Glu669Lys
  • NP_001364207.1:p.Glu669Lys
  • NP_001364208.1:p.Glu669Lys
  • NP_001364209.1:p.Glu669Lys
  • LRG_98:g.12297G>A
  • NC_000011.9:g.36596859G>A
Protein change:
E669K
Links:
dbSNP: rs878853004
NCBI 1000 Genomes Browser:
rs878853004
Molecular consequence:
  • NM_000448.3:c.2005G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2005G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2005G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2005G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2005G>A - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004570841Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 18, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome.

Bai X, Liu J, Zhang Z, Liu C, Zhang Y, Tang W, Dai R, Wu J, Tang X, Zhang Y, Ding Y, Jiang L, Zhao X.

Immunol Res. 2016 Apr;64(2):497-507. doi: 10.1007/s12026-015-8723-4.

PubMed [citation]
PMID:
26476733
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004570841.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 669 of the RAG1 protein (p.Glu669Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 24144642, 26476733, 28747913, 32655540). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 235297). 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. 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: 11133745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024