NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp) AND Histiocytic medullary reticulosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 9, 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:: RCV002282448.1

Allele description [Variation Report for NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp)]

NM_000448.3(RAG1):c.1228C>T (p.Arg410Trp)

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.1228C>T (p.Arg410Trp)

HGVS:

NC_000011.10:g.36574532C>T
NG_007528.1:g.11520C>T
NM_000448.3:c.1228C>TMANE SELECT
NM_001377277.1:c.1228C>T
NM_001377278.1:c.1228C>T
NM_001377279.1:c.1228C>T
NM_001377280.1:c.1228C>T
NP_000439.2:p.Arg410Trp
NP_001364206.1:p.Arg410Trp
NP_001364207.1:p.Arg410Trp
NP_001364208.1:p.Arg410Trp
NP_001364209.1:p.Arg410Trp
LRG_98t1:c.1228C>T
LRG_98:g.11520C>T
NC_000011.9:g.36596082C>T
NM_000448.2:c.1228C>T

Protein change:

R410W

Links:

dbSNP: rs758288006

NCBI 1000 Genomes Browser:

rs758288006

Molecular consequence:

NM_000448.3:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.1228C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Histiocytic medullary reticulosis
Synonyms:: Omenn syndrome; Reticuloendotheliosis familial with eosinophilia; Severe combined immunodeficiency with hypereosinophilia
Identifiers:: MONDO: MONDO:0011338; MedGen: C2700553; Orphanet: 39041; OMIM: 603554

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002570283	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 9, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11133745, 24290284, 24406074, 28769923, 30046960, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002570283

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 9, 2022)

germline

clinical testing

PubMed (6)
[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

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, Arkwright PD, Baniyash M, Brooks EG, Conley ME, Cortes P, Duse M, Fasth A, Filipovich AM, Infante AJ, Jones A, Mazzolari E, Muller SM, Pasic S, Rechavi G, Sacco MG, Santagata S, et al.

Blood. 2001 Jan 1;97(1):81-8.

PubMed [citation]

PMID:: 11133745

A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.

Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, et al.

J Allergy Clin Immunol. 2014 Apr;133(4):1099-108. doi: 10.1016/j.jaci.2013.10.007. Epub 2013 Nov 28.

PubMed [citation]

PMID:: 24290284
PMCID:: PMC4005599

See all PubMed Citations (6)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV002570283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This RAG1 variant (rs758288006) is rare (<0.1%) in a large population dataset (gnomAD: 3/250794 total alleles; 0.002%; no homozygotes) and has been reported in ClinVar. This variant has been observed in a compound heterozygous state in unrelated individuals with RAG1-related immune disorders. In addition, a different variant that disrupts this amino acid residue (p.Arg410Gln) has been reported in an individual with atypical SCID/Omenn syndrome. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is strongly conserved across all vertebrate species assessed. V(D)J recombination activity of RAG1 protein containing the p.Arg410Trp variant was significantly reduced in a heterologous cell-based assay. Bioinformatic analysis predicts that this variant would not affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. This variant alone is not predicted to cause disease. We consider this variant to be likely 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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