RAG2 p.Arg167Ser

The c.501A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Arginine by Serine at amino acid 167 (p.Arg167Ser). The highest population minor allele frequency in gnomAD v4 is 0.0001941 (1/5152 alleles) in the Ashkenazi Jewish population. As this is a known bottleneck population, it will not be considered here for PM2_Supporting. As no other alleles have been reported in other populations, PM2 at the supporting level is applied (Absence in GnomAD). 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. This variant has been detected in one individual with SCID, reported by Invitae in ClinVar. This individual is compound heterozygous for p.Gly95Arg, a likely pathogenic variant according to SCID VCEP specifications. Both parents were tested, and the phase is confirmed: 1 point. PM3_Moderate (Internal lab contributor). No clinical features were described; Not possible to evaluate for PP4. 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, PM1_Supporting, and PM3_Moderate. (VCEP specifications version 1).