NM_000536.4(RAG2):c.595G>T (p.Glu199Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 1, 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:: RCV000547792.7

Allele description [Variation Report for NM_000536.4(RAG2):c.595G>T (p.Glu199Ter)]

NM_000536.4(RAG2):c.595G>T (p.Glu199Ter)

Gene:

RAG2:recombination activating 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000536.4(RAG2):c.595G>T (p.Glu199Ter)

HGVS:

NC_000011.10:g.36593574C>A
NG_007573.1:g.9663G>T
NG_033154.1:g.4082C>A
NM_000536.4:c.595G>TMANE SELECT
NM_001243785.2:c.595G>T
NM_001243786.2:c.595G>T
NP_000527.2:p.Glu199Ter
NP_001230714.1:p.Glu199Ter
NP_001230715.1:p.Glu199Ter
LRG_99:g.9663G>T
NC_000011.9:g.36615124C>A
NM_000536.3:c.595G>T

Protein change:

E199*

Links:

dbSNP: rs748727021

NCBI 1000 Genomes Browser:

rs748727021

Molecular consequence:

NM_000536.4:c.595G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243785.2:c.595G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243786.2:c.595G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000638117	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21624848, 29772310, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638117

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 1, 2022)

germline

clinical testing

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

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

Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.

Dalal I, Tasher D, Somech R, Etzioni A, Garti BZ, Lev D, Cohen S, Somekh E, Leshinsky-Silver E.

Clin Immunol. 2011 Sep;140(3):284-90. doi: 10.1016/j.clim.2011.04.011. Epub 2011 May 7.

PubMed [citation]

PMID:: 21624848

Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.

Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, Burns S, Al-Herz W, Noroski L, Walter JE, Gennery AR, van der Burg M, Notarangelo LD, Lee YN.

J Allergy Clin Immunol. 2019 Feb;143(2):726-735. doi: 10.1016/j.jaci.2018.04.027. Epub 2018 Jun 18.

PubMed [citation]

PMID:: 29772310
PMCID:: PMC6295349

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000638117.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAG2 protein in which other variant(s) (p.Glu480*) have been determined to be pathogenic (PMID: 21624848, 29772310). 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: 463972). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is present in population databases (rs748727021, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu199*) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 329 amino acid(s) of the RAG2 protein.

#	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: Feb 28, 2024

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