The NM_000215.4(JAK3):c.2291C>T variant in JAK3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 764 (p.Pro764Leu). The filtering allele frequency (the upper threshold of the 95% CI of 3/33008) of the c.2291C>T variant is 0.00002408 for African/African American subpopulation chromosomes by gnomAD v.4.0.0, which is lower than the threshold (<0.000115) defined by the ClinGen Severe Combined immunodeficiency Disease Variant Curation Expert Panel (SCID VCEP) for JAK3 variants (PM2_supporting). One patient was found reported on Clinvar; however, the affected status is unknown (VCV000863482.6). This variant does not meet the criteria to be classified as pathogenic, likely pahogenic, benign or likely benign for T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID JAK3 VCEP (PM2_supporting) ; therefore is classified as a variant of unknown significance (VUS) for this disease. (VCEP specifications version 1).