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NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 25, 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:
RCV001065315.8

Allele description [Variation Report for NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp)]

NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp)

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.1228C>T (p.Arg410Trp)
HGVS:
  • NC_000011.10:g.36574532C>T
  • NG_007528.1:g.11520C>T
  • NM_000448.3:c.1228C>TMANE SELECT
  • NM_001377277.1:c.1228C>T
  • NM_001377278.1:c.1228C>T
  • NM_001377279.1:c.1228C>T
  • NM_001377280.1:c.1228C>T
  • NP_000439.2:p.Arg410Trp
  • NP_001364206.1:p.Arg410Trp
  • NP_001364207.1:p.Arg410Trp
  • NP_001364208.1:p.Arg410Trp
  • NP_001364209.1:p.Arg410Trp
  • LRG_98t1:c.1228C>T
  • LRG_98:g.11520C>T
  • NC_000011.9:g.36596082C>T
  • NM_000448.2:c.1228C>T
Protein change:
R410W
Links:
dbSNP: rs758288006
NCBI 1000 Genomes Browser:
rs758288006
Molecular consequence:
  • NM_000448.3:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.1228C>T - 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
SCV001230271Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Sep 25, 2023) 		germlineclinical testing

PubMed (7)
[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

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, Schwarz K, Schulz AS, Hoenig M, Sparber-Sauer M, Gatz SA, Denzer C, Blanche S, Moshous D, Picard C, Horn BN, de Villartay JP, Cavazzana M, Debatin KM, Friedrich W, Fischer A, Cowan MJ.

Blood. 2014 Jan 9;123(2):281-9. doi: 10.1182/blood-2013-01-476432. Epub 2013 Oct 21. Erratum in: Blood. 2018 Dec 6;132(23):2527. doi: 10.1182/blood-2018-10-882217.

PubMed [citation]
PMID:
24144642
PMCID:
PMC3953035

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A(+++) Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Dobbs K, Tabellini G, Calzoni E, Patrizi O, Martinez P, Giliani SC, Moratto D, Al-Herz W, Cancrini C, Cowan M, Bleesing J, Booth C, Buchbinder D, Burns SO, Chatila TA, Chou J, Daza-Cajigal V, Ott de Bruin LM, de la Morena M, Di Matteo G, Finocchi A, Geha R, et al.

Front Immunol. 2017;8:798. doi: 10.3389/fimmu.2017.00798. Erratum in: Front Immunol. 2017 Oct 10;8:1244. doi: 10.3389/fimmu.2017.01244.

PubMed [citation]
PMID:
28769923
PMCID:
PMC5511964
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001230271.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the RAG1 protein (p.Arg410Trp). This variant is present in population databases (rs758288006, gnomAD 0.002%). This missense change has been observed in individuals with severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency (PMID: 24144642, 24290284, 24406074, 28769923). ClinVar contains an entry for this variant (Variation ID: 859249). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). This variant disrupts the p.Arg410 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 11971977, 24290284, 24406074). 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: Sep 29, 2024