Variant: NM_000536.4(RAG2):c.104G>C (p.Gly35Ala)

CA214209

36716 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: d37e95ae-57f1-4e72-9555-f88de74a1511

Approved on: 2024-05-13

Published on: 2024-05-13

HGVS expressions

NM_000536.4:c.104G>C
NM_000536.4(RAG2):c.104G>C (p.Gly35Ala)
NC_000011.10:g.36594065C>G
CM000673.2:g.36594065C>G
NC_000011.9:g.36615615C>G
CM000673.1:g.36615615C>G
NC_000011.8:g.36572191C>G
NG_007573.1:g.9172G>C
NG_033154.1:g.4573C>G
ENST00000527033.6:c.104G>C
ENST00000529083.2:c.104G>C
ENST00000532616.2:c.104G>C
ENST00000311485.8:c.104G>C
ENST00000311485.7:c.104G>C
ENST00000524423.1:n.131+4037G>C
ENST00000527033.5:c.104G>C
ENST00000529083.1:c.104G>C
ENST00000618712.4:c.104G>C
NM_000536.3:c.104G>C
NM_001243785.1:c.104G>C
NM_001243786.1:c.104G>C
NM_001243785.2:c.104G>C
NM_001243786.2:c.104G>C

Pathogenic

• Met criteria codes: PP4 PM5_Supporting PM2_Supporting PM3_Strong PM1_Supporting PS3_Moderate

• Not Met criteria codes: PS1 BS2

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.104G>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glycine by Alanine at amino acid 35 (p.Gly35Ala). The filtering allele frequency (the upper threshold of the 95% CI of 23/1179974 alleles) of the c.104G>C variant in RAG2 is 0.00001295 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 recombination activity assay showed activity of this variant compared to wildtype RAG2 is 22.1% (SEM 3.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). This variant has been detected in at least 5 individuals with SCID/Leaky SCID/Omenn syndrome in the literature. Of those individuals, one (Proband 35, PMID: 30778343) is compound heterozygous for p.K58STer73, which is at least LP according to our specifications. Mother and Father are carriers; the trans phase is confirmed. 1 point. Another proband (Proband 9, PMID: 29772310) is a compound heterozygous with E437K, classified as Likely Pathogenic according to SCID VCEP. This patient is being evaluated in the p.Glu437Lys variant curation, so it will not be counted here to avoid circularity. Additionally, 3 individuals were homozygous for the variant (probands 6, 7, and 8, PMID: 29772310), reaching the maximum of 1 point for homozygous occurrence; The total is 2 points, PM3_Strong. At least one patient present: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + * Decreased presence of TCRVα7.2 in CD3+ T lymphocytes 0.5 points. The total is 1 point, and then PP4 is met (PMID: 29772310). Another missense variant [NM_000536.4(RAG2):c.104G>T (p.Gly35Val)] in the same codon has been reported. The variant was classified as Likely Pathogenic by the ClinGen SCID VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM1_Supporting, PS3_Moderate, PM3_Strong, PP4, PM5_Supporting (VCEP specifications version 1).

Met criteria codes

• PP4: At least one patient present: diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + Decreased presence of TCRVα7.2 in CD3+ T lymphocytes 0.5 points, total is 1 point, PP4 is met (PMID: 29772310).
• PM5_Supporting: Another missense variant [NM_000536.4(RAG2):c.104G>T (p.Gly35Val)] in the same codon has been reported; The variant was classified as Likely Pathogenic by the ClinGen SCID VCEP (PM5_Supporting).
• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 23/1179974 alleles) of the c.104G>C variant in RAG2 is 0.00001295 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).
• PM3_Strong: This variant has been detected in at least 5 individuals with SCID/Leaky SCID/Omenn syndrome in the literature. Of those individuals, one (Proband 35, PMID: 30778343) is compound heterozygous for p.K58STer73, which is at least LP according to our specifications. Mother and Father are carriers; the trans phase is confirmed. 1 point. Another proband (Proband 9, PMID: 29772310) is a compound heterozygous with E437K, classified as Likely Pathogenic according to SCID VCEP. This patient is being evaluated in the NM_000536.4(RAG2):c.1309G>A (p.Glu437Lys) variant curation, so it will not be counted here to avoid circularity. Additionally, 3 individuals were homozygous for the variant (probands 6, 7, and 8, PMID: 29772310) reaching the maximum of 1 point for homozygous occurrence; Total of 2 points, PM3_Strong.
• 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.
• PS3_Moderate: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 22.1% (SEM 3.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline