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NM_000536.4(RAG2):c.653T>A (p.Ile218Asn) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 26, 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:
RCV002851216.3

Allele description [Variation Report for NM_000536.4(RAG2):c.653T>A (p.Ile218Asn)]

NM_000536.4(RAG2):c.653T>A (p.Ile218Asn)

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.653T>A (p.Ile218Asn)
HGVS:
  • NC_000011.10:g.36593516A>T
  • NG_007573.1:g.9721T>A
  • NG_033154.1:g.4024A>T
  • NM_000536.4:c.653T>AMANE SELECT
  • NM_001243785.2:c.653T>A
  • NM_001243786.2:c.653T>A
  • NP_000527.2:p.Ile218Asn
  • NP_000527.2:p.Ile218Asn
  • NP_001230714.1:p.Ile218Asn
  • NP_001230715.1:p.Ile218Asn
  • LRG_99t1:c.653T>A
  • LRG_99:g.9721T>A
  • LRG_99p1:p.Ile218Asn
  • NC_000011.9:g.36615066A>T
  • NM_000536.2:c.653T>A
Protein change:
I218N
Molecular consequence:
  • NM_000536.4:c.653T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243785.2:c.653T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243786.2:c.653T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV003217895Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jun 26, 2022) 		germlineclinical testing

PubMed (3)
[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

Why newborn screening for severe combined immunodeficiency is essential: a case report.

Adeli MM, Buckley RH.

Pediatrics. 2010 Aug;126(2):e465-9. doi: 10.1542/peds.2009-3659. Epub 2010 Jul 5.

PubMed [citation]
PMID:
20603253

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A(+++) Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Dobbs K, Tabellini G, Calzoni E, Patrizi O, Martinez P, Giliani SC, Moratto D, Al-Herz W, Cancrini C, Cowan M, Bleesing J, Booth C, Buchbinder D, Burns SO, Chatila TA, Chou J, Daza-Cajigal V, Ott de Bruin LM, de la Morena M, Di Matteo G, Finocchi A, Geha R, et al.

Front Immunol. 2017;8:798. doi: 10.3389/fimmu.2017.00798. Erratum in: Front Immunol. 2017 Oct 10;8:1244. doi: 10.3389/fimmu.2017.01244.

PubMed [citation]
PMID:
28769923
PMCID:
PMC5511964
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003217895.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This missense change has been observed in individuals with severe combined immunodeficiency (PMID: 20603253, 28769923). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 218 of the RAG2 protein (p.Ile218Asn).

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

Last Updated: Sep 29, 2024