Variant: NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)

CA380144219

427020 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: af4a5023-b029-4d29-a204-f133d99d23f0

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.193G>T
NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)
NC_000011.10:g.36593976C>A
CM000673.2:g.36593976C>A
NC_000011.9:g.36615526C>A
CM000673.1:g.36615526C>A
NC_000011.8:g.36572102C>A
NG_007573.1:g.9261G>T
NG_033154.1:g.4484C>A
ENST00000311485.8:c.193G>T
ENST00000311485.7:c.193G>T
ENST00000524423.1:n.131+4126G>T
ENST00000527033.5:c.193G>T
ENST00000529083.1:c.193G>T
ENST00000618712.4:c.193G>T
NM_000536.3:c.193G>T
NM_001243785.1:c.193G>T
NM_001243786.1:c.193G>T
NM_001243785.2:c.193G>T
NM_001243786.2:c.193G>T

Likely Pathogenic

• Met criteria codes: PM1_Supporting PM3_Supporting PP4 PS3_Moderate PM2_Supporting

• Not Met criteria codes: 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 NM_000536.4:c.193G>T variant in RAG2 is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 65 (p.Asp74Tyr). The variant has been reported in one individual with SCID. The individual was homozygous of this variant (PM3_Supporting, PMID 21624848). The individual had a T-B-NK+ lymphocyte profile and showed reduced T-cell proliferation under PHA stimulation, which supports a diagnosis of leaky/atypical SCID (PP4, PMID 21624848). The highest population minor allele frequency of this variant in gnomAD v2.1.1 is 0.000008791 (1/113758 alleles) in the European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.0000588) for PM2_Supporting. No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant resides within the core domain (amino acids 1-383) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP. (PM1_Supporting). An in vitro recombination activity assay shows that the relevant activity of the p.D65Y variant compared to wildtype RAG2 is 6.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate (PS3_Moderate, PMID 29772310). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PP4, PM3_Supporting, PM2_Supporting, PM1_Supporting, and PS3_Moderate (VCEP specifications version 1.0).

Met criteria codes

• PM1_Supporting: This variant resides within the core domain (amino acids 1-383) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP. (PM1_Supporting).
• PM3_Supporting: One individual with SCID was homozygous of this variant (0.5pt, PMID 21624848). 0.5pt in total, PM3_Supporting is met.
• PP4: One individual was homozygous for this variant. The individual had T-B-NK+ lymphocyte profiles (0.5pt) and showed reduced T-cell proliferation under PHA treatment. Based on the clinical features, a diagnosis of leaky/atypical SCID is confirmed (0.5pt). 1pt in total, PP4 is met. (PMID 21624848)
• PS3_Moderate: An in vitro recombination activity assay shows that the relevant activity of the p.D65Y variant compared to wildtype RAG2 is 6.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate. (PMID 29772310)
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113758 alleles) in European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.0000588) for PM2_Supporting. No homozygous individual has been observed in the gnomAD v2.1.1. (PM2_Supporting)

Not Met criteria codes

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