NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 22, 2024
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:: RCV001389162.6

Allele description [Variation Report for NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)]

NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)

Gene:

RAG1:recombination activating 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)

HGVS:

NC_000011.10:g.36576171T>C
NG_007528.1:g.13159T>C
NM_000448.2:c.2867T>C
NM_000448.3:c.2867T>CMANE SELECT
NM_001377277.1:c.2867T>C
NM_001377278.1:c.2867T>C
NM_001377279.1:c.2867T>C
NM_001377280.1:c.2867T>C
NP_000439.2:p.Ile956Thr
NP_001364206.1:p.Ile956Thr
NP_001364207.1:p.Ile956Thr
NP_001364208.1:p.Ile956Thr
NP_001364209.1:p.Ile956Thr
LRG_98t1:c.2867T>C
LRG_98:g.13159T>C
NC_000011.9:g.36597721T>C
NM_000448.3:c.2867T>C

Protein change:

I956T

Links:

dbSNP: rs182385524

NCBI 1000 Genomes Browser:

rs182385524

Molecular consequence:

NM_000448.3:c.2867T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.2867T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.2867T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.2867T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.2867T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined immunodeficiency with skin 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; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; Severe combined immunodeficiency due to complete RAG1/2 deficiency
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
SCV001590428	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 22, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16960852, 28083621, 24290284, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590428

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 22, 2024)

germline

clinical testing

PubMed (4)
[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

RAG-dependent primary immunodeficiencies.

Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A.

Hum Mutat. 2006 Dec;27(12):1174-84. Review.

PubMed [citation]

PMID:: 16960852

Mutation c.256_257delAA in RAG1 Gene in Polish Children with Severe Combined Immunodeficiency: Diversity of Clinical Manifestations.

Szaflarska A, Rutkowska-Zapała M, Kotula M, Gruca A, Grabowska A, Lenart M, Surman M, Trzyna E, Mordel A, Pituch-Noworolska A, Siedlar M.

Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):177-183. doi: 10.1007/s00005-016-0447-1. Epub 2017 Jan 12.

PubMed [citation]

PMID:: 28083621
PMCID:: PMC5334423

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590428.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 956 of the RAG1 protein (p.Ile956Thr). This variant is present in population databases (rs182385524, gnomAD 0.01%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 16960852, 24290284, 28083621). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1075542). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). For these reasons, this variant has been 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: May 16, 2025

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