NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 28, 2021
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:: RCV002526041.2

Allele description [Variation Report for NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)]

NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)

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.193G>T (p.Asp65Tyr)

Other names:

NM_000536.4(RAG2):c.193G>T; p.Asp65Tyr

HGVS:

NC_000011.10:g.36593976C>A
NG_007573.1:g.9261G>T
NG_033154.1:g.4484C>A
NM_000536.4:c.193G>TMANE SELECT
NM_001243785.2:c.193G>T
NM_001243786.2:c.193G>T
NP_000527.2:p.Asp65Tyr
NP_001230714.1:p.Asp65Tyr
NP_001230715.1:p.Asp65Tyr
LRG_99:g.9261G>T
NC_000011.9:g.36615526C>A
NM_000536.3:c.193G>T

Protein change:

D65Y

Links:

dbSNP: rs909264507

NCBI 1000 Genomes Browser:

rs909264507

Molecular consequence:

NM_000536.4:c.193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243785.2:c.193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243786.2:c.193G>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on catalytic protein function [Variation Ontology: 0008]

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
SCV003439691	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 28, 2021)	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

SCV003439691

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 28, 2021)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003439691.1

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 65 of the RAG2 protein (p.Asp65Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 21624848). ClinVar contains an entry for this variant (Variation ID: 427020). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG2 protein function. Experimental studies have shown that this missense change affects RAG2 function (PMID: 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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