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NM_000448.3(RAG1):c.2615T>G (p.Leu872Ter) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 28, 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:
RCV001385792.7

Allele description [Variation Report for NM_000448.3(RAG1):c.2615T>G (p.Leu872Ter)]

NM_000448.3(RAG1):c.2615T>G (p.Leu872Ter)

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.2615T>G (p.Leu872Ter)
HGVS:
  • NC_000011.10:g.36575919T>G
  • NG_007528.1:g.12907T>G
  • NM_000448.3:c.2615T>GMANE SELECT
  • NM_001377277.1:c.2615T>G
  • NM_001377278.1:c.2615T>G
  • NM_001377279.1:c.2615T>G
  • NM_001377280.1:c.2615T>G
  • NP_000439.2:p.Leu872Ter
  • NP_001364206.1:p.Leu872Ter
  • NP_001364207.1:p.Leu872Ter
  • NP_001364208.1:p.Leu872Ter
  • NP_001364209.1:p.Leu872Ter
  • LRG_98:g.12907T>G
  • NC_000011.9:g.36597469T>G
Protein change:
L872*
Links:
dbSNP: rs749360497
NCBI 1000 Genomes Browser:
rs749360497
Molecular consequence:
  • NM_000448.3:c.2615T>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377277.1:c.2615T>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377278.1:c.2615T>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377279.1:c.2615T>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001377280.1:c.2615T>G - 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
SCV001585755Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 28, 2022) 		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

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

Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development.

Yu X, Almeida JR, Darko S, van der Burg M, DeRavin SS, Malech H, Gennery A, Chinn I, Markert ML, Douek DC, Milner JD.

J Allergy Clin Immunol. 2014 Apr;133(4):1109-15. doi: 10.1016/j.jaci.2013.11.018. Epub 2014 Jan 7.

PubMed [citation]
PMID:
24406074
PMCID:
PMC3972286
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585755.4

#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.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. ClinVar contains an entry for this variant (Variation ID: 1072942). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 11133745). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu872*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 172 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