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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004591384	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24290284, 8810255, 10701853, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004591384

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 1, 2023)

germline

clinical testing

PubMed (4)
[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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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).

#	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: Oct 8, 2024

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