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NM_000448.3(RAG1):c.2095C>T (p.Arg699Trp) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 11, 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:
RCV000548870.6

Allele description [Variation Report for NM_000448.3(RAG1):c.2095C>T (p.Arg699Trp)]

NM_000448.3(RAG1):c.2095C>T (p.Arg699Trp)

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.2095C>T (p.Arg699Trp)
HGVS:
  • NC_000011.10:g.36575399C>T
  • NG_007528.1:g.12387C>T
  • NM_000448.3:c.2095C>TMANE SELECT
  • NM_001377277.1:c.2095C>T
  • NM_001377278.1:c.2095C>T
  • NM_001377279.1:c.2095C>T
  • NM_001377280.1:c.2095C>T
  • NP_000439.1:p.Arg699Trp
  • NP_000439.2:p.Arg699Trp
  • NP_001364206.1:p.Arg699Trp
  • NP_001364207.1:p.Arg699Trp
  • NP_001364208.1:p.Arg699Trp
  • NP_001364209.1:p.Arg699Trp
  • LRG_98t1:c.2095C>T
  • LRG_98:g.12387C>T
  • LRG_98p1:p.Arg699Trp
  • NC_000011.9:g.36596949C>T
  • NM_000448.2:c.2095C>T
  • NM_000448.3:c.2095C>T
  • P15918:p.Arg699Trp
Protein change:
R699W
Links:
UniProtKB: P15918#VAR_067276; UniProtKB/Swiss-Prot: VAR_067276; dbSNP: rs199474676
NCBI 1000 Genomes Browser:
rs199474676
Molecular consequence:
  • NM_000448.3:c.2095C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2095C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2095C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2095C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2095C>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
SCV000638114Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 11, 2023) 		germlineclinical testing

PubMed (6)
[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

Highly variable clinical phenotypes of hypomorphic RAG1 mutations.

Avila EM, Uzel G, Hsu A, Milner JD, Turner ML, Pittaluga S, Freeman AF, Holland SM.

Pediatrics. 2010 Nov;126(5):e1248-52. doi: 10.1542/peds.2009-3171. Epub 2010 Oct 18.

PubMed [citation]
PMID:
20956421

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Lee PP, Chan KW, Chen TX, Jiang LP, Wang XC, Zeng HS, Chen XY, Liew WK, Chen J, Chu KM, Chan LL, Shek L, Lee AC, Yu HH, Li Q, Xu CG, Sultan-Ugdoracion G, Latiff ZA, Latiff AH, Jirapongsananuruk O, Ho MH, Lee TL, et al.

J Clin Immunol. 2011 Apr;31(2):281-96. doi: 10.1007/s10875-010-9489-z. Epub 2010 Dec 24.

PubMed [citation]
PMID:
21184155
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000638114.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 699 of the RAG1 protein (p.Arg699Trp). This variant is present in population databases (rs199474676, gnomAD 0.02%). This missense change has been observed in individuals with RAG1-related diseases (PMID: 20956421, 21184155, 21771083, 24122031, 24290284). This variant is also known as 2219C>T. ClinVar contains an entry for this variant (Variation ID: 68689). 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.Arg699 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 24290284), which suggests that this may be a clinically significant amino acid residue. 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: Jun 23, 2024