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NM_000448.3(RAG1):c.2689C>T (p.Arg897Ter) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 5, 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:
RCV001041560.14

Allele description [Variation Report for NM_000448.3(RAG1):c.2689C>T (p.Arg897Ter)]

NM_000448.3(RAG1):c.2689C>T (p.Arg897Ter)

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.2689C>T (p.Arg897Ter)
HGVS:
  • NC_000011.10:g.36575993C>T
  • NG_007528.1:g.12981C>T
  • NM_000448.3:c.2689C>TMANE SELECT
  • NM_001377277.1:c.2689C>T
  • NM_001377278.1:c.2689C>T
  • NM_001377279.1:c.2689C>T
  • NM_001377280.1:c.2689C>T
  • NP_000439.1:p.Arg897Ter
  • NP_000439.2:p.Arg897Ter
  • NP_001364206.1:p.Arg897Ter
  • NP_001364207.1:p.Arg897Ter
  • NP_001364208.1:p.Arg897Ter
  • NP_001364209.1:p.Arg897Ter
  • LRG_98t1:c.2689C>T
  • LRG_98:g.12981C>T
  • LRG_98p1:p.Arg897Ter
  • NC_000011.9:g.36597543C>T
  • NM_000448.2:c.2689C>T
Protein change:
R897*
Links:
dbSNP: rs757797994
NCBI 1000 Genomes Browser:
rs757797994
Molecular consequence:
  • NM_000448.3:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377277.1:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377278.1:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377279.1:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377280.1:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001205184Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 5, 2023) 		germlineclinical testing

PubMed (8)
[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

RAG mutations in human B cell-negative SCID.

Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR.

Science. 1996 Oct 4;274(5284):97-9.

PubMed [citation]
PMID:
8810255

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
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001205184.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg897*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acid(s) of the RAG1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of severe combined immunodeficiency or Omenn syndrome (PMID: 8810255, 11520796, 24144642, 25516070). ClinVar contains an entry for this variant (Variation ID: 488725). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RAG1 function (PMID: 11520796). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Trp959*) 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. 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: Oct 26, 2024