NM_000448.3(RAG1):c.1682G>A (p.Arg561His) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 5, 2023
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:: RCV001384043.5

Allele description [Variation Report for NM_000448.3(RAG1):c.1682G>A (p.Arg561His)]

NM_000448.3(RAG1):c.1682G>A (p.Arg561His)

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.1682G>A (p.Arg561His)

HGVS:

NC_000011.10:g.36574986G>A
NG_007528.1:g.11974G>A
NM_000448.3:c.1682G>AMANE SELECT
NM_001377277.1:c.1682G>A
NM_001377278.1:c.1682G>A
NM_001377279.1:c.1682G>A
NM_001377280.1:c.1682G>A
NP_000439.1:p.Arg561His
NP_000439.2:p.Arg561His
NP_001364206.1:p.Arg561His
NP_001364207.1:p.Arg561His
NP_001364208.1:p.Arg561His
NP_001364209.1:p.Arg561His
LRG_98t1:c.1682G>A
LRG_98:g.11974G>A
LRG_98p1:p.Arg561His
NC_000011.9:g.36596536G>A
NM_000448.2:c.1682G>A
P15918:p.Arg561His

Protein change:

R561H; ARG561HIS

Links:

UniProtKB: P15918#VAR_008889; OMIM: 179615.0005; dbSNP: rs104894284

NCBI 1000 Genomes Browser:

rs104894284

Molecular consequence:

NM_000448.3:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.1682G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001583412	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16211094, 28783691, 14670978, 9630231, 11133745, 24290284, 26596586, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001583412

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 5, 2023)

germline

clinical testing

PubMed (8)
[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

A variant of SCID with specific immune responses and predominance of gamma delta T cells.

Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, Mascart F, Schmitt-Graeff A, Niemeyer C, Fisch P.

J Clin Invest. 2005 Nov;115(11):3140-8. Epub 2005 Oct 6.

PubMed [citation]

PMID:: 16211094
PMCID:: PMC1242191

Characterization of T and B cell repertoire diversity in patients with RAG deficiency.

Lee YN, Frugoni F, Dobbs K, Tirosh I, Du L, Ververs FA, Ru H, Ott de Bruin L, Adeli M, Bleesing JH, Buchbinder D, Butte MJ, Cancrini C, Chen K, Choo S, Elfeky RA, Finocchi A, Fuleihan RL, Gennery AR, El-Ghoneimy DH, Henderson LA, Al-Herz W, et al.

Sci Immunol. 2016 Dec 16;1(6). doi:pii: eaah6109. 10.1126/sciimmunol.aah6109. Epub 2016 Dec 16.

PubMed [citation]

PMID:: 28783691
PMCID:: PMC5586490

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001583412.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 561 of the RAG1 protein (p.Arg561His). This variant is present in population databases (rs104894284, gnomAD 0.003%). This missense change has been observed in individuals with severe combined immunodeficiency (SCID) and Omenn syndrome (PMID: 9630231, 16211094, 24290284, 28783691). ClinVar contains an entry for this variant (Variation ID: 13143). 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: 9630231, 14670978, 24290284). This variant disrupts the p.Arg561 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9630231, 11133745, 24290284, 26596586). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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