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NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) AND Recombinase activating gene 1 deficiency

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 14, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV003398651.1

Allele description [Variation Report for NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)]

NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)

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.1331C>T (p.Ala444Val)
Other names:
NM_000448.3(RAG1):c.1331C>T
HGVS:
  • NC_000011.10:g.36574635C>T
  • NG_007528.1:g.11623C>T
  • NM_000448.3:c.1331C>TMANE SELECT
  • NM_001377277.1:c.1331C>T
  • NM_001377278.1:c.1331C>T
  • NM_001377279.1:c.1331C>T
  • NM_001377280.1:c.1331C>T
  • NP_000439.1:p.Ala444Val
  • NP_000439.2:p.Ala444Val
  • NP_001364206.1:p.Ala444Val
  • NP_001364207.1:p.Ala444Val
  • NP_001364208.1:p.Ala444Val
  • NP_001364209.1:p.Ala444Val
  • LRG_98t1:c.1331C>T
  • LRG_98:g.11623C>T
  • LRG_98p1:p.Ala444Val
  • NC_000011.9:g.36596185C>T
  • NM_000448.2:c.1331C>T
  • P15918:p.Ala444Val
Protein change:
A444V
Links:
UniProtKB: P15918#VAR_025977; UniProtKB/Swiss-Prot: VAR_025977; dbSNP: rs199474685
NCBI 1000 Genomes Browser:
rs199474685
Molecular consequence:
  • NM_000448.3:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.1331C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Recombinase activating gene 1 deficiency
Identifiers:
MONDO: MONDO:0000572; MedGen: CN375631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004102815ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen SCID ACMG Specifications RAG1 V1.0.0)		Pathogenic
(Nov 14, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004102815.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199; PM1). The popmax allele frequency is 0.00003266 (1/30614 alleles) in the South Asisan population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). At least 11 patients have been reported with this variant (PMIDs: 26596586, 24290284, 23085344, 17572155, 11133745, 36596882, 29410113), including patient 11 of PMID: 26596586 whom meets diagnostic criteria for SCID with a T-B-NK+ lymphocyte subset profile which is specific to recombinase activating gene 1 deficiency (PP4). Six patients are homozygous for this variant (PMIDs: 24290284, 17572155,11133745; 1pt maximum) and five are compound heterozygous (PMIDs: 26596586, 23085344, 11133745, 36596882, 29410113), harboring this variant as well as c.256_257 (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM2_supporting, PP4, PM3_Strong, PS3_Moderate. (VCEP specifications version 1).

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

Last Updated: Aug 4, 2024