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NM_000448.3(RAG1):c.2291G>A (p.Arg764His) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 18, 2022
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:
RCV001871951.5

Allele description [Variation Report for NM_000448.3(RAG1):c.2291G>A (p.Arg764His)]

NM_000448.3(RAG1):c.2291G>A (p.Arg764His)

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.2291G>A (p.Arg764His)
Other names:
NM_000448.3(RAG1):c.2291G>A; p.Arg764His
HGVS:
  • NC_000011.10:g.36575595G>A
  • NG_007528.1:g.12583G>A
  • NM_000448.2:c.2291G>A
  • NM_000448.3:c.2291G>AMANE SELECT
  • NM_001377277.1:c.2291G>A
  • NM_001377278.1:c.2291G>A
  • NM_001377279.1:c.2291G>A
  • NM_001377280.1:c.2291G>A
  • NP_000439.2:p.Arg764His
  • NP_001364206.1:p.Arg764His
  • NP_001364207.1:p.Arg764His
  • NP_001364208.1:p.Arg764His
  • NP_001364209.1:p.Arg764His
  • LRG_98t1:c.2291G>A
  • LRG_98:g.12583G>A
  • NC_000011.9:g.36597145G>A
Protein change:
R764H
Links:
dbSNP: rs768809293
NCBI 1000 Genomes Browser:
rs768809293
Molecular consequence:
  • NM_000448.3:c.2291G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2291G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2291G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2291G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2291G>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
SCV002178446Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jul 18, 2022) 		germlineclinical testing

PubMed (5)
[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

RAG1 deficiency may present clinically as selective IgA deficiency.

Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, Nishida N, Kanegane H, Wada T, Yachie A, Ohara O, Morio T, Notarangelo LD, Imai K, Nonoyama S.

J Clin Immunol. 2015 Apr;35(3):280-8. doi: 10.1007/s10875-015-0146-4. Epub 2015 Mar 6.

PubMed [citation]
PMID:
25739914

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
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002178446.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 764 of the RAG1 protein (p.Arg764His). This variant is present in population databases (rs768809293, gnomAD 0.002%). This missense change has been observed in individual(s) with selective immunoglobulin A deficiency (PMID: 25739914). ClinVar contains an entry for this variant (Variation ID: 1050623). 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 expected to disrupt RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 25739914). This variant disrupts the p.Arg764 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 24290284, 25104208, 33954879), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024