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NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 1, 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:
RCV003764567.2

Allele description [Variation Report for NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys)]

NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys)

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.2164G>A (p.Glu722Lys)
HGVS:
  • NC_000011.10:g.36575468G>A
  • NG_007528.1:g.12456G>A
  • NM_000448.2:c.2164G>A
  • NM_000448.3:c.2164G>AMANE SELECT
  • NM_001377277.1:c.2164G>A
  • NM_001377278.1:c.2164G>A
  • NM_001377279.1:c.2164G>A
  • NM_001377280.1:c.2164G>A
  • NP_000439.2:p.Glu722Lys
  • NP_001364206.1:p.Glu722Lys
  • NP_001364207.1:p.Glu722Lys
  • NP_001364208.1:p.Glu722Lys
  • NP_001364209.1:p.Glu722Lys
  • LRG_98t1:c.2164G>A
  • LRG_98:g.12456G>A
  • NC_000011.9:g.36597018G>A
  • NM_000448.3:c.2164G>A
  • P15918:p.Glu722Lys
Protein change:
E722K; GLU722LYS
Links:
UniProtKB: P15918#VAR_007804; OMIM: 179615.0001; dbSNP: rs28933392
NCBI 1000 Genomes Browser:
rs28933392
Molecular consequence:
  • NM_000448.3:c.2164G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2164G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2164G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2164G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2164G>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
SCV004591384Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 1, 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

A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.

Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, et al.

J Allergy Clin Immunol. 2014 Apr;133(4):1099-108. doi: 10.1016/j.jaci.2013.10.007. Epub 2013 Nov 28.

PubMed [citation]
PMID:
24290284
PMCID:
PMC4005599

RAG mutations in human B cell-negative SCID.

Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR.

Science. 1996 Oct 4;274(5284):97-9.

PubMed [citation]
PMID:
8810255
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004591384.1

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

Description

This variant is present in population databases (rs28933392, gnomAD 0.004%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RAG1 function (PMID: 8810255, 24290284). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13139). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 8810255, 10701853). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 722 of the RAG1 protein (p.Glu722Lys).

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

Last Updated: Oct 20, 2024