Variant: NM_000536.4(RAG2):c.328A>C (p.Met110Leu)

CA214221

36720 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: cb3e3eda-44e4-4e9c-99b8-f08c01e01d89

Approved on: 2024-05-13

Published on: 2024-05-13

HGVS expressions

NM_000536.4:c.328A>C
NM_000536.4(RAG2):c.328A>C (p.Met110Leu)
NC_000011.10:g.36593841T>G
CM000673.2:g.36593841T>G
NC_000011.9:g.36615391T>G
CM000673.1:g.36615391T>G
NC_000011.8:g.36571967T>G
NG_007573.1:g.9396A>C
NG_033154.1:g.4349T>G
ENST00000527033.6:c.328A>C
ENST00000529083.2:c.328A>C
ENST00000532616.2:c.328A>C
ENST00000311485.8:c.328A>C
ENST00000311485.7:c.328A>C
ENST00000524423.1:n.131+4261A>C
ENST00000529083.1:c.328A>C
ENST00000618712.4:c.328A>C
NM_000536.3:c.328A>C
NM_001243785.1:c.328A>C
NM_001243786.1:c.328A>C
NM_001243785.2:c.328A>C
NM_001243786.2:c.328A>C

Uncertain Significance

• Met criteria codes: PM1_Supporting PM2_Supporting

• Not Met criteria codes: PP4 PM5 PS3

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 RAG2 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.328A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Methionine by Leucine at amino acid 110 (p.Met110Leu). The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032 alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting. The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least a supporting level). So, PS3 is not applied at any strength level. (PMID: 29772310). At least one patient in the literature seems to be a carrier of this variant (PMID: 29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1).

Met criteria codes

• PM1_Supporting: This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.
• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032 alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

Not Met criteria codes

• PP4: At least one patient in the literature seems to be a carrier of this variant (PMID: 29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met.
• PM5: A different missense variant in the same codon: c.328A>G (p.Met110Val) has been reported in ClinVar as a Variant of Uncertain Significance; However, this variant has not yet been classified according to the SCID VCEP specifications; so PM5 is not met at any level of the evidence at this moment.
• PS3: The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least supporting level). So, PS3 is not applied at any level of strength. (PMID: 29772310, PS3_notmet).