NM_000448.3(RAG1):c.2917C>T (p.Arg973Cys) AND Severe combined immunodeficiency disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 22, 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:: RCV004702616.1

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:: Severe combined immunodeficiency disease
Synonyms:: Severe combined immunodeficiency; Severe Combined Immune Deficiency
Identifiers:: MONDO: MONDO:0015974; MeSH: D016511; MedGen: C0085110; Human Phenotype Ontology: HP:0004430

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005203034	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 22, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24290284, 32888943, 35503492 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005203034

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 22, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

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

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005203034.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: RAG1 c.2917C>T (p.Arg973Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250542 control chromosomes (gnomAD). c.2917C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency (e.g. Lee_2014, Platt_2021, Barreiros_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete loss of recombination activity (Lee_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24290284, 32888943, 35503492). ClinVar contains an entry for this variant (Variation ID: 855458). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: May 25, 2025

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