Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000448.3(RAG1):c.424C>T (p.Arg142Ter)

CA5949977

626157 (ClinVar)

Gene: RAG1 (HGNC:5896)

Condition: recombinase activating gene 1 deficiency (MONDO:0000572)

Inheritance Mode: Autosomal recessive inheritance

UUID: 028ba414-0b6f-44c4-b287-6e3a75e482d0

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000448.3(RAG1):c.424C>T (p.Arg142Ter)

NM_000448.3:c.424C>T

NC_000011.10:g.36573728C>T

CM000673.2:g.36573728C>T

NC_000011.9:g.36595278C>T

CM000673.1:g.36595278C>T

NC_000011.8:g.36551854C>T

NG_007528.1:g.10716C>T

ENST00000299440.6:c.424C>T

ENST00000299440.5:c.424C>T

ENST00000534663.1:c.424C>T

NM_000448.2:c.424C>T

NM_001377277.1:c.424C>T

NM_001377278.1:c.424C>T

NM_001377279.1:c.424C>T

NM_001377280.1:c.424C>T

Pathogenic

PM3 PM2_Supporting PVS1

PS3 PP4

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The nonsense variant NM_000448.3(RAG1):c.424C>T (p.Arg142Ter) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense-mediated decay but does truncate 86% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). The popmax allele frequency is 0.00004007 (1/24954 alleles) in the African/African American population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). This variant has been reported in at least seven patients with atypical SCID or Omenn syndrome (PMIDs: 30877075, 33225392, 30307608, 25849362, 20109747, 24290284, 17075247) however in all cases there is insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). This variant has been reported homozygous in at least two Omenn syndrome patients (PMIDs: 33225392, 30307608; 1pt; PM3). Five additional atypical SCID or Omenn syndrome cases have been reported compound heterozygous for this variant (PMIDs: 30877075, 25849362, 20109747, 24290284, 17075247). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Arg142Ter was 9.0% of wild type +/- 4.0 (PMID: 24290284). However, because no patient has been identified meeting the PP4 criteria PS3 is not applied at any strength. 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: PVS1, PM3 and PM2_Supporting. (VCEP specifications version 1).

PM3

This variant has been reported homozygous in at least two Omenn syndrome patients (PMIDs: 33225392, 30307608; 1pt; PM3). Five additional atypical SCID or Omenn syndrome cases have been reported compound heterozygous for this variant (PMIDs: 30877075, 25849362, 20109747, 24290284, 17075247). The second variant in these cases have not yet been classified by the ClinGen SCID VCEP: Thr477Ser, M458SfsX34, and R396H (potential to score 0-0.5pt each), as well as Val779Met (potential to score 0.25-1pt) and are not considered here to avoid circularity.

PM2_Supporting

The popmax allele frequency is 0.00004007 (1/24954 alleles) in the African/African American population, which is below the SCID VCEP established threshold of <0.000102.

PVS1

Nonsense variant NM_000448.3(RAG1):c.424C>T (p.Arg142Ter) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in NMD but does truncate 86% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1).

PS3

A-MuLV– transformed Rag1−/− tg.Eμ-bcl2 pro-B cells, containing a single integration of the pMX-INV GFP cassette flanked by RSSs, which were further transduced with retroviral vectors encoding wild-type or mutant hRAG1 or wild-type mouse Rag1 (mRag1) and hCD2 as a reporter. VDJ recombination activity was measured by normalizing GFP expression to that observed in the presence of wild-type hRAG1. Mean recombination activity for Arg142Ter was 9.0% of wild type +/- 4.0 (PMID: 24290284; PS3_moderate). However, because no patient has been identified meeting the PP4 criteria PS3 is not applied at any strength.

PP4

This variant has been reported in at least seven patients with atypical SCID or Omenn syndrome (PMIDs: 30877075, 33225392, 30307608, 25849362, 20109747, 24290284, 17075247) however in all cases there is insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet).

Curation History

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