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.2904C>A (p.Asn968Lys)

CA214200

36713 (ClinVar)

Gene: RAG1

Condition: recombinase activating gene 1 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a1b11909-e7c8-4f9c-88e1-27318aa4a348

Approved on: 2024-05-07

Published on: 2024-05-07

HGVS expressions

NM_000448.3:c.2904C>A

NM_000448.3(RAG1):c.2904C>A (p.Asn968Lys)

NC_000011.10:g.36576208C>A

CM000673.2:g.36576208C>A

NC_000011.9:g.36597758C>A

CM000673.1:g.36597758C>A

NC_000011.8:g.36554334C>A

NG_007528.1:g.13196C>A

ENST00000697713.1:c.2904C>A

ENST00000697714.1:c.2904C>A

ENST00000697715.1:c.2904C>A

ENST00000299440.6:c.2904C>A

ENST00000299440.5:c.2904C>A

ENST00000524423.1:n.132-237G>T

ENST00000534663.1:c.2789+115C>A

NM_000448.2:c.2904C>A

NM_001377277.1:c.2904C>A

NM_001377278.1:c.2904C>A

NM_001377279.1:c.2904C>A

NM_001377280.1:c.2904C>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.2904C>A is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 968 (p.Asn968Lys). This missense variant is located in the core domain (amino acids 387-1011)(PM1_Supporting). The highest population minor allele frequency in gnomAD v4 is 8.993e-7 (1/1112012 alleles) in European Non-Finnish population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient with Omenn syndrome was found heterozygous for c.3016C>G, p.N968K & c.2387C>T, p.R759C (not classified by SCID VCEP yet) (PMID: 15908971):PM3 not evaluated. 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 highest population minor allele frequency in gnomAD v4 is 8.993e-7 (1/1112012 alleles) in European Non-Finnish population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting).

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