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NM_000448.3(RAG1):c.2974A>G (p.Lys992Glu) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 29, 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:
RCV000542154.8

Allele description [Variation Report for NM_000448.3(RAG1):c.2974A>G (p.Lys992Glu)]

NM_000448.3(RAG1):c.2974A>G (p.Lys992Glu)

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.2974A>G (p.Lys992Glu)
HGVS:
  • NC_000011.10:g.36576278A>G
  • NG_007528.1:g.13266A>G
  • NM_000448.3:c.2974A>GMANE SELECT
  • NM_001377277.1:c.2974A>G
  • NM_001377278.1:c.2974A>G
  • NM_001377279.1:c.2974A>G
  • NM_001377280.1:c.2974A>G
  • NP_000439.1:p.Lys992Glu
  • NP_000439.2:p.Lys992Glu
  • NP_001364206.1:p.Lys992Glu
  • NP_001364207.1:p.Lys992Glu
  • NP_001364208.1:p.Lys992Glu
  • NP_001364209.1:p.Lys992Glu
  • LRG_98t1:c.2974A>G
  • LRG_98:g.13266A>G
  • LRG_98p1:p.Lys992Glu
  • NC_000011.9:g.36597828A>G
  • NM_000448.2:c.2974A>G
Protein change:
K992E
Links:
dbSNP: rs539590514
NCBI 1000 Genomes Browser:
rs539590514
Molecular consequence:
  • NM_000448.3:c.2974A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2974A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2974A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2974A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2974A>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000638116Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Sep 29, 2023) 		germlineclinical testing

PubMed (4)
[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

Clinical application of DNA microarrays: molecular diagnosis and HLA matching of an Amish child with severe combined immune deficiency.

Strauss KA, Puffenberger EG, Bunin N, Rider NL, Morton MC, Eastman JT 3rd, Morton DH.

Clin Immunol. 2008 Jul;128(1):31-8. doi: 10.1016/j.clim.2008.02.016. Epub 2008 Apr 28.

PubMed [citation]
PMID:
18442948

Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.

Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP.

Blood. 2001 May 1;97(9):2772-6.

PubMed [citation]
PMID:
11313270
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638116.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 992 of the RAG1 protein (p.Lys992Glu). This variant is present in population databases (rs539590514, gnomAD 0.002%). This missense change has been observed in individuals with Omenn syndrome (PMID: 11313270, 18442948, 24290284). ClinVar contains an entry for this variant (Variation ID: 372488). 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: 11313270, 24290284). 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: Oct 13, 2024