NM_000448.3(RAG1):c.2258A>T (p.His753Leu) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 23, 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:: RCV002271397.1

Allele description [Variation Report for NM_000448.3(RAG1):c.2258A>T (p.His753Leu)]

NM_000448.3(RAG1):c.2258A>T (p.His753Leu)

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.2258A>T (p.His753Leu)

HGVS:

NC_000011.10:g.36575562A>T
NG_007528.1:g.12550A>T
NM_000448.3:c.2258A>TMANE SELECT
NM_001377277.1:c.2258A>T
NM_001377278.1:c.2258A>T
NM_001377279.1:c.2258A>T
NM_001377280.1:c.2258A>T
NP_000439.1:p.His753Leu
NP_000439.2:p.His753Leu
NP_001364206.1:p.His753Leu
NP_001364207.1:p.His753Leu
NP_001364208.1:p.His753Leu
NP_001364209.1:p.His753Leu
LRG_98t1:c.2258A>T
LRG_98:g.12550A>T
LRG_98p1:p.His753Leu
NC_000011.9:g.36597112A>T
NM_000448.2:c.2258A>T
P15918:p.His753Leu

Protein change:

H753L

Links:

UniProtKB: P15918#VAR_025984; UniProtKB/Swiss-Prot: VAR_025984; dbSNP: rs199474687

NCBI 1000 Genomes Browser:

rs199474687

Molecular consequence:

NM_000448.3:c.2258A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377277.1:c.2258A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377278.1:c.2258A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377279.1:c.2258A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377280.1:c.2258A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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hypothetical protein E3N88_02096 [Mikania micrantha]
hypothetical protein E3N88_02096 [Mikania micrantha]
gi|1770259833|gb|KAD7478960.1||gnl| ZYD|E3N88_02096

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002556102	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11971977, 11133745, 25976673 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002556102

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 23, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Mutational analysis of all conserved basic amino acids in RAG-1 reveals catalytic, step arrest, and joining-deficient mutants in the V(D)J recombinase.

Huye LE, Purugganan MM, Jiang MM, Roth DB.

Mol Cell Biol. 2002 May;22(10):3460-73.

PubMed [citation]

PMID:: 11971977
PMCID:: PMC133788

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

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002556102.1

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

Description

Variant summary: RAG1 c.2258A>T (p.His753Leu) results in a non-conservative amino acid change located in the Zinc Finger B region of the Core Central (CD) domain (Kumar_2015) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). c.2258A>T has been reported in the literature in at least one compound heterozygous individual affected with atypical Severe Combined Immunodeficiency (Villa_2001). These data do not allow any conclusion about variant significance. One publication reports that disruption of the highly conserved corresponding amino acid in mouse RAG1 severely impacted DNA binding (15-50 fold decrease, Huye_2002). One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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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