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NM_000448.3(RAG1):c.2228del (p.Asn743fs) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 19, 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:
RCV003799199.2

Allele description [Variation Report for NM_000448.3(RAG1):c.2228del (p.Asn743fs)]

NM_000448.3(RAG1):c.2228del (p.Asn743fs)

Gene:
RAG1:recombination activating 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11p12
Genomic location:
Preferred name:
NM_000448.3(RAG1):c.2228del (p.Asn743fs)
HGVS:
  • NC_000011.10:g.36575532del
  • NG_007528.1:g.12520del
  • NM_000448.3:c.2228delMANE SELECT
  • NM_001377277.1:c.2228del
  • NM_001377278.1:c.2228del
  • NM_001377279.1:c.2228del
  • NM_001377280.1:c.2228del
  • NP_000439.1:p.Asn743Ilefs
  • NP_000439.2:p.Asn743fs
  • NP_001364206.1:p.Asn743fs
  • NP_001364207.1:p.Asn743fs
  • NP_001364208.1:p.Asn743fs
  • NP_001364209.1:p.Asn743fs
  • LRG_98t1:c.2228del
  • LRG_98:g.12520del
  • LRG_98p1:p.Asn743Ilefs
  • NC_000011.9:g.36597079del
  • NC_000011.9:g.36597082del
  • NM_000448.2:c.2228delA
Protein change:
N743fs
Molecular consequence:
  • NM_000448.3:c.2228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377277.1:c.2228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377278.1:c.2228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377279.1:c.2228del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377280.1:c.2228del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004586251Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 19, 2023) 		germlineclinical testing

PubMed (4)
[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

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

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004586251.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAG1 protein in which other variant(s) (p.R959*) have been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with RAG1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Asn743Ilefs*7) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 301 amino acid(s) of the RAG1 protein.

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

Last Updated: Sep 29, 2024