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]

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

CA219800

68681 (ClinVar)

Gene: RAG1

Condition: recombinase activating gene 1 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4c48f76d-1958-49ce-9365-ac8fe43b0175

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000448.3:c.1331C>T

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

NC_000011.10:g.36574635C>T

CM000673.2:g.36574635C>T

NC_000011.9:g.36596185C>T

CM000673.1:g.36596185C>T

NC_000011.8:g.36552761C>T

NG_007528.1:g.11623C>T

ENST00000299440.6:c.1331C>T

ENST00000299440.5:c.1331C>T

ENST00000534663.1:c.1331C>T

NM_000448.2:c.1331C>T

NM_001377277.1:c.1331C>T

NM_001377278.1:c.1331C>T

NM_001377279.1:c.1331C>T

NM_001377280.1:c.1331C>T

Pathogenic

PS3_Moderate PM2_Supporting PP4 PM1 PM3_Strong

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 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).

PS3_Moderate

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 Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate)

PM2_Supporting

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).

PP4

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).

PM1

PM3_Strong

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_257del (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong)

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