The c.678_679del (p.Cys227ProfsTer?) (NM_000215.4) variant in JAK3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003577 (1/27956) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, meeting this criterion (PM2_Supporting). One patient compound heterozygous with variant c.1767C>T (PMID: 23384681). It was not evaluated at this moment because the pathogenic level was already reached. One homozygous patient described on ClinVar (3billion, T-B+ severe combined immunodeficiency due to JAK3 deficiency) affected status: yes. Hepatosplenomegaly (present), Pneumonia (present) - (0.5pt). PM3_Supporting. Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total=1pt, PP4. (PMID: 23384681). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PP4, PM2_supporting and PM3_supporting. (VCEP specifications version 1).