NM_000448.3(RAG1):c.256_257del (p.Lys86fs) AND Severe combined immunodeficiency disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 23, 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:: RCV002222473.1

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:: Severe combined immunodeficiency disease (SCID)
Synonyms:: Severe combined immunodeficiency; Bubble boy disease; Severe Combined Immune Deficiency
Identifiers:: MONDO: MONDO:0015974; MeSH: D016511; MedGen: C0085110; Human Phenotype Ontology: HP:0004430

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002500598	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17572155, 11121059, 11313270 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002500598

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 23, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes.

Haq IJ, Steinberg LJ, Hoenig M, van der Burg M, Villa A, Cant AJ, Middleton PG, Gennery AR.

Clin Immunol. 2007 Aug;124(2):165-9. Epub 2007 Jun 14.

PubMed [citation]

PMID:: 17572155

N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains.

Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A.

Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14572-7.

PubMed [citation]

PMID:: 11121059
PMCID:: PMC18960

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500598.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: RAG1 c.256_257delAA (p.Lys86ValfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251098 control chromosomes. c.256_257delAA has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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