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NM_000448.3(RAG1):c.256_257del (p.Lys86fs) AND RAG1-related disorder

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Apr 28, 2017
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:
RCV000779060.5

Allele description [Variation Report for NM_000448.3(RAG1):c.256_257del (p.Lys86fs)]

NM_000448.3(RAG1):c.256_257del (p.Lys86fs)

Gene:
RAG1:recombination activating 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11p12
Genomic location:
Preferred name:
NM_000448.3(RAG1):c.256_257del (p.Lys86fs)
Other names:
NM_000448.3(RAG1):c.256_257del; p.Lys86fs
HGVS:
  • NC_000011.10:g.36573560_36573561del
  • NG_007528.1:g.10548_10549del
  • NM_000448.3:c.256_257delMANE SELECT
  • NM_001377277.1:c.256_257del
  • NM_001377278.1:c.256_257del
  • NM_001377279.1:c.256_257del
  • NM_001377280.1:c.256_257del
  • NP_000439.2:p.Lys86fs
  • NP_001364206.1:p.Lys86fs
  • NP_001364207.1:p.Lys86fs
  • NP_001364208.1:p.Lys86fs
  • NP_001364209.1:p.Lys86fs
  • LRG_98:g.10548_10549del
  • NC_000011.9:g.36595110_36595111del
  • NM_000448.2:c.256_257delAA
  • NM_000448.3:c.256_257del
Links:
OMIM: 179615.0013; dbSNP: rs772962160
NCBI 1000 Genomes Browser:
rs772962160
Molecular consequence:
  • NM_000448.3:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377277.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377278.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377279.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377280.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
RAG1-related disorder
Synonyms:
RAG1-Related Disorders; RAG1-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000915526Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Pathogenic
(Apr 28, 2017) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV005348414PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Oct 28, 2023) 		germlineclinical testing

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

Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders.

Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, Nugent D, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Csomos K, Rosen L, Browne S, Walter JE, Notarangelo LD, Hill HR, Kumánovics A.

J Clin Immunol. 2015 Feb;35(2):119-24. doi: 10.1007/s10875-014-0121-5. Epub 2014 Dec 17.

PubMed [citation]
PMID:
25516070
PMCID:
PMC4479182
See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915526.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The RAG1 c.256_257delAA (p.Lys86ValfsTer33) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Lys86ValfsTer33 variant has been reported in five studies in which it is found in a total of 14 individuals with RAG1-related disorders, including in eight in a homozygous state, five in a compound heterozygous state, and one in a heterozygous state (Abraham et al. 2013; Lee et al. 2014; Buchbinder et al. 2015; Walter et al. 2015; Brauer et al. 2016). Homozygous individuals included six with severe combined immune deficiency (SCID) and two with Omenn syndrome (OS); compound heterozygous individuals included two with OS, one with common variable immunodeficiency disorder (CVID), two with combined immune deficiency with granuloma and/or autoimmunity (CID-G/A); the heterozygote had an unspecified immunodeficiency. Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Lys86ValfsTer33 variant protein was found to have approximately three percent of wild type RAG1 recombinase activity when analyzed in pro-B cells that were deficient for wild type RAG1 (Abraham et al. 2013; Buchbinder et al. 2015; Brauer et al. 2016). Based on the evidence and potential impact of frameshift variants, the p.Lys86ValfsTer33 variant is classified as pathogenic for RAG1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From PreventionGenetics, part of Exact Sciences, SCV005348414.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The RAG1 c.256_257delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys86Valfs*33). This variant has been reported as causative for autosomal recessive Omenn syndrome, as well as sever combined immunodeficiency syndrome (Table 1, referred to as deletion 368-369, Villa et al. 1998. PubMed ID: 9630231; Table 2, Kutukculer et al. 2012. PubMed ID: 22424479; Sharapova et al. 2013. PubMed ID: 23085344; IJspeert et al. 2014. PubMed ID: 24418478; Buchbinder et al. 2015. PubMed ID: 25516070). It is reported to be a founder mutation in Slavic populations that originated in Poland (Sharapova et al 2020. PubMed ID: 32655540). Experimental studies indicated this variant reduces RAG1 activity compared to wildtype (referred to as c.368_369delAA, Figure 1, IJspeert et al. 2014. PubMed ID: 24418478). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36595109-TAA-T). Frameshift variants in RAG1 are expected to be pathogenic. This variant is interpreted as pathogenic.

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

Last Updated: Oct 8, 2024