U.S. flag

An official website of the United States government

NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) AND Severe combined immunodeficiency disease

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 20, 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:
RCV002281904.2

Allele description [Variation Report for NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)]

NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)

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.1331C>T (p.Ala444Val)
Other names:
NM_000448.3(RAG1):c.1331C>T
HGVS:
  • NC_000011.10:g.36574635C>T
  • NG_007528.1:g.11623C>T
  • NM_000448.3:c.1331C>TMANE SELECT
  • NM_001377277.1:c.1331C>T
  • NM_001377278.1:c.1331C>T
  • NM_001377279.1:c.1331C>T
  • NM_001377280.1:c.1331C>T
  • NP_000439.1:p.Ala444Val
  • NP_000439.2:p.Ala444Val
  • NP_001364206.1:p.Ala444Val
  • NP_001364207.1:p.Ala444Val
  • NP_001364208.1:p.Ala444Val
  • NP_001364209.1:p.Ala444Val
  • LRG_98t1:c.1331C>T
  • LRG_98:g.11623C>T
  • LRG_98p1:p.Ala444Val
  • NC_000011.9:g.36596185C>T
  • NM_000448.2:c.1331C>T
  • P15918:p.Ala444Val
Protein change:
A444V
Links:
UniProtKB: P15918#VAR_025977; UniProtKB/Swiss-Prot: VAR_025977; dbSNP: rs199474685
NCBI 1000 Genomes Browser:
rs199474685
Molecular consequence:
  • NM_000448.3:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Severe combined immunodeficiency disease (SCID)
Synonyms:
Severe combined immunodeficiency; Bubble boy disease; Severe Combined Immune Deficiency
Identifiers:
MONDO: MONDO:0015974; MeSH: D016511; MedGen: C0085110; Human Phenotype Ontology: HP:0004430

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002570605Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 20, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes.

Haq IJ, Steinberg LJ, Hoenig M, van der Burg M, Villa A, Cant AJ, Middleton PG, Gennery AR.

Clin Immunol. 2007 Aug;124(2):165-9. Epub 2007 Jun 14.

PubMed [citation]
PMID:
17572155

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, Arkwright PD, Baniyash M, Brooks EG, Conley ME, Cortes P, Duse M, Fasth A, Filipovich AM, Infante AJ, Jones A, Mazzolari E, Muller SM, Pasic S, Rechavi G, Sacco MG, Santagata S, et al.

Blood. 2001 Jan 1;97(1):81-8.

PubMed [citation]
PMID:
11133745
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570605.1

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

Description

Variant summary: RAG1 c.1331C>T (p.Ala444Val) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250826 control chromosomes. c.1331C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency/Atypical SCID/Omenn syndrome (example, Villa_2001, Haq_2007, Sharapova_2012, Firtina_2020). 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 (example, Lee_2014). The most pronounced variant effect results in 1.4% of normal VDJ recombination activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Aug 4, 2024