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NM_000448.3(RAG1):c.2917C>T (p.Arg973Cys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 5, 2024
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:
RCV001060735.9

Allele description [Variation Report for NM_000448.3(RAG1):c.2917C>T (p.Arg973Cys)]

NM_000448.3(RAG1):c.2917C>T (p.Arg973Cys)

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.2917C>T (p.Arg973Cys)
HGVS:
  • NC_000011.10:g.36576221C>T
  • NG_007528.1:g.13209C>T
  • NM_000448.3:c.2917C>TMANE SELECT
  • NM_001377277.1:c.2917C>T
  • NM_001377278.1:c.2917C>T
  • NM_001377279.1:c.2917C>T
  • NM_001377280.1:c.2917C>T
  • NP_000439.2:p.Arg973Cys
  • NP_001364206.1:p.Arg973Cys
  • NP_001364207.1:p.Arg973Cys
  • NP_001364208.1:p.Arg973Cys
  • NP_001364209.1:p.Arg973Cys
  • LRG_98t1:c.2917C>T
  • LRG_98:g.13209C>T
  • NC_000011.9:g.36597771C>T
  • NM_000448.2:c.2917C>T
Protein change:
R973C
Links:
dbSNP: rs1389614116
NCBI 1000 Genomes Browser:
rs1389614116
Molecular consequence:
  • NM_000448.3:c.2917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2917C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined immunodeficiency with skin 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; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; Severe combined immunodeficiency due to complete RAG1/2 deficiency
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
SCV001225442Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 5, 2024) 		germlineclinical testing

PubMed (8)
[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

Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency.

Platt CD, Zaman F, Bainter W, Stafstrom K, Almutairi A, Reigle M, Weeks S, Geha RS, Chou J; International Consortium for Immunodeficiencies.

J Allergy Clin Immunol. 2021 Feb;147(2):723-726. doi: 10.1016/j.jaci.2020.08.022. Epub 2020 Sep 2.

PubMed [citation]
PMID:
32888943
PMCID:
PMC7870529

SCID and Other Inborn Errors of Immunity with Low TRECs - the Brazilian Experience.

Barreiros LA, Sousa JL, Geier C, Leiss-Piller A, Kanegae MPP, França TT, Boisson B, Lima AM, Costa-Carvalho BT, Aranda CS, de Moraes-Pinto MI, Segundo GRS, Ferreira JFS, Tavares FS, Guimarães FATM, Toledo EC, da Matta Ain AC, Moreira IF, Soldatelli G, Grumach AS, de Barros Dorna M, Weber CW, et al.

J Clin Immunol. 2022 Aug;42(6):1171-1192. doi: 10.1007/s10875-022-01275-9. Epub 2022 May 3.

PubMed [citation]
PMID:
35503492
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225442.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 973 of the RAG1 protein (p.Arg973Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency and with combined immunodeficiency and autoimmunity (PMID: 24290284, 32888943, 35503492, 36279417; Invitae). ClinVar contains an entry for this variant (Variation ID: 855458). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284, 36279417). This variant disrupts the p.Arg973 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313270, 28747913, 30307608). 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: May 25, 2025