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.2291G>A (p.Arg764His)

CA5950243

1050623 (ClinVar)

Gene: RAG1

Condition: recombinase activating gene 1 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2215cc43-ed77-4af1-bece-04508cd80701

Approved on: 2024-02-26

Published on: 2024-02-26

HGVS expressions

NM_000448.3:c.2291G>A

NM_000448.3(RAG1):c.2291G>A (p.Arg764His)

NC_000011.10:g.36575595G>A

CM000673.2:g.36575595G>A

NC_000011.9:g.36597145G>A

CM000673.1:g.36597145G>A

NC_000011.8:g.36553721G>A

NG_007528.1:g.12583G>A

ENST00000697713.1:c.2291G>A

ENST00000697714.1:c.2291G>A

ENST00000697715.1:c.2291G>A

ENST00000299440.6:c.2291G>A

ENST00000299440.5:c.2291G>A

ENST00000524423.1:n.508C>T

ENST00000534663.1:c.2291G>A

NM_000448.2:c.2291G>A

NM_001377277.1:c.2291G>A

NM_001377278.1:c.2291G>A

NM_001377279.1:c.2291G>A

NM_001377280.1:c.2291G>A

Uncertain Significance

PM1_Supporting PM2_Supporting

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

NM_000448.3(RAG1):c.2291G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 764 (p.Arg764His). This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting). The filtering allele frequency (the upper threshold of the 95% CI of 22/1180042) of the c.2291G>A variant in RAG1 is 0.00001213 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Two missense variants c. 2291G>C, p.R764P (PMID: 24290284); c.2290C>T , p.Arg764Cys (PMID: 25104208) (not classified by SCID VCEP yet) in the same codon have been reported. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_Supporting (VCEP specifications version 1).

PM1_Supporting

This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting).

PM2_Supporting

The filtering allele frequency (the upper threshold of the 95% CI of 22/1180042) of the c.2291G>A variant in RAG1 is 0.00001213 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

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