Variant: NM_000536.4(RAG2):c.283G>A (p.Gly95Arg)

CA122861

13133 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 9b823cc5-9cb7-4569-8109-9c81036d1e31

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.283G>A
NM_000536.4(RAG2):c.283G>A (p.Gly95Arg)
NC_000011.10:g.36593886C>T
CM000673.2:g.36593886C>T
NC_000011.9:g.36615436C>T
CM000673.1:g.36615436C>T
NC_000011.8:g.36572012C>T
NG_007573.1:g.9351G>A
NG_033154.1:g.4394C>T
ENST00000311485.8:c.283G>A
ENST00000311485.7:c.283G>A
ENST00000524423.1:n.131+4216G>A
ENST00000529083.1:c.283G>A
ENST00000618712.4:c.283G>A
NM_000536.3:c.283G>A
NM_001243785.1:c.283G>A
NM_001243786.1:c.283G>A
NM_001243785.2:c.283G>A
NM_001243786.2:c.283G>A

Likely Pathogenic

• Met criteria codes: PS3_Moderate PP4 PM1_Supporting PM2_Supporting PM3

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.283G>A variant in RAG2 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 95 (p.Gly94Arg). This variant has a population max filtering allele frequency of 0.000007010, which is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant is located in the core domain (amino acids 1-383) of RAG2, which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). In experimental studies, this variant demonstrates a mean recombination activity that is 0.3% of wildtype, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% of wildtype activity) for PS3_Moderate. This variant has been reported in several individuals with severe combined immunodeficiency or Omenn syndrome. Two unrelated individuals are homozygous for this variant (PMID: 33599911, 30307608) (0.5p + 0.5p). Three individuals carry this variant along with a second co-occurring RAG2 variant (p.Trp453Arg (phase unknown, 0.25p), p.Glu480* (phase unknown, 0p), p.Arg229Trp (confirmed in trans, 0p)) (PMID: 10891502, 31838659, 15025726). (0.5p + 0.5p +0.25p = 1.25p, PS3). The p.Trp453Arg variant has been classified as Likely Pathogenic, whereas the p.Glu480* and p.Arg229Trp variants have not yet been classified by the ClinGen SCID VCEP. At least one of these reported patients meets PP4 criteria established by the ClinGen SCID VCEP: T-B-NK+ lymphocyte subset profile (0.5p), meets clinical diagnostic criteria for SCID (0.5p), testing via large SCID panel or exome sequencing (0.5p): 1.5p (PMID: 33599911). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM1_Supporting, PM2_Supporting, PS3_Moderate, PP4, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

Met criteria codes

• PS3_Moderate: This variant displays recombination activity that is 0.3% of wildtype which is below the SCID VCEP threshold (<25% of wildtype activity) for PS3_moderate. To apply PS3, at least one patient must meet PP4 criteria and we have at least one patient meeting PP4. Therefore PS3_moderate criteria is met.
• PP4: At least one patient reported that meets PP4 criteria (1 point) - PMID: 30307608. Patient in PMID: 33599911 also meets PP4 (1.5p). Other patients reported but we only need 1 patient meeting PP4 to apply the criteria and none of the other reported patients would exceed 1 point (therefore the max we would reach is PP4 with no modification). Therefore, PP4 is met at regular strength (1-2p = PP4 at regular strength).
• PM1_Supporting: This missense variant is located in the core domain (amino acids 1-383) and therefore qualifies for PM1_supporting as outlined in the SCID VCEP specifications for RAG2
• PM2_Supporting: gnomAD popmax filtering allele frequency is 0.000007010 which is lower than the threshold for PM2_supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). No homozygotes observed.
• PM3: Homozygous proband (PMID: 30307608): 0.5p. Homozygous proband (PMID: 33599911): 0.5p. (note the two homozygous probands are unrelated. Also note that another homozygous proband in PMID: 31838659 is likely same patient as PMID: 33599911, not counting again toward PM3). This variant also co-occurs with p.Trp453Arg (classified LP by SCID VCEP), phase unknown (PMID: 10891502): 0.25p. Total 0.5p + 0.5p + 0.25p = 1.25p which qualifies for PM3 at regular strength. There is potential for additional points here as well: -This variant co-occurs (phase unknown) with p.E480X (not yet classified by VCEP) - if p.E480X turns out to be pathogenic, this would be worth an additional 0.5p -This variant co-occurs in trans (confirmed by parental testing) with p.Arg229Trp (not yet classified by VCEP). p.Arg229Trp is rare variant (1 allele gnomAD) which would be at LEAST VUS and given the number of papers in the literature for this variant reporting on patients, could be LP/P. If VUS, this is worth additional 0.25p. If LP/P, this is worth additional 1p. So potential to add 0.25-1p for this co-occurrence. Therefore, there is potential to add an additional 0.25-1.5p to PM3 which would result in total of 2.75 points so there is potential to upgrade to PM3_Strong once these additional variants are classified.