Variant: NM_000215.4(JAK3):c.1796T>G (p.Val599Gly)

624608 (ClinVar)

Gene: JAK3

Condition: T-B+ severe combined immunodeficiency due to JAK3 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: f0ce65af-4ee6-412b-a75d-8b5147663418

HGVS expressions

NM_000215.4:c.1796T>G
NM_000215.4(JAK3):c.1796T>G (p.Val599Gly)

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2_Supporting

• Not Met criteria codes: 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 JAK3 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) missense variant has been reported in a TlowB+NKlow patient (patient 4 of PMID: 30032486), diagnosed with leaky SCID (reported in PMID: 31456805), including low CD3+ cells (733.5 cells/ul), reduced, but detectable, proliferative response to PHA (>10 < 30% of the control), and absence of maternal engraftment. Patient cells also had defective STAT5 phosphorylation after IL2 or IL15 stimulation. This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (PP4). Patient 4 (PMID: 30032486) is compound heterozygous for p.V599G and p.W709R (Classified VUS by the SCID VCEP) confirmed in trans, but this co-occurrence of variants is insufficient for the PM3 criteria. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PP4. (VCEP specifications version 1).

Met criteria codes

• PP4_Moderate: This variant was identified in at least one TlowB+NKlow (CD3+ 733.5 cells/ul, CD19+ 4,126.7 cells/ul, CD16+/CD56+ 70.0 cells/ul) patient (patient 4 of PMID: 30032486) by two different custom Ion Torrent panels for a total of 42 genes related to a broad spectrum of PID (0.5pt). The patient met diagnostic criteria for leaky SCID (reported in PMID: 31456805), including CD3+ 733.5 cells/ul and reduced, but detectable, proliferative response to PHA (> 10 < 30% of the control), plus absence of maternal engraftment (0.5pt) and had defective STAT5 phosphorylation after IL2 or IL15 stimulation (1pt). This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 2pt; PP4_moderate).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PM3: Pt 4 (first reported in PMID: 30032486) is compound heterozygous for p.V599G and p.W709R (classified VUS by SCID VCEP), confirmed in trans (0.25pt; PM3_NotMet).

Approved on: 2024-01-17

Published on: 2024-01-17