Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000215.4(JAK3):c.1744C>T (p.Arg582Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA214079

36415 (ClinVar)

Gene: JAK3

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

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9fc56b24-3ecc-42eb-88fc-a558478c49b0

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000215.4:c.1744C>T

NM_000215.4(JAK3):c.1744C>T (p.Arg582Trp)

NC_000019.10:g.17837171G>A

CM000681.2:g.17837171G>A

NC_000019.9:g.17947980G>A

CM000681.1:g.17947980G>A

NC_000019.8:g.17808980G>A

NG_007273.1:g.15821C>T

ENST00000458235.7:c.1744C>T

ENST00000458235.5:c.1744C>T

ENST00000527031.5:n.1834C>T

ENST00000527670.5:c.1744C>T

ENST00000534444.1:c.1744C>T

NM_000215.3:c.1744C>T

Likely Pathogenic

PM2_Supporting PM4_Supporting PM3 PP4_Moderate

BS2 PM5

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000215.4(JAK3):c.1744C>T variant is predicted to cause the Arg582Trp missense substitution, however it has been observed in patient cDNA to cause an in-frame deletion of 213bp (71 amino acids; p.Ser568_Leu638del) due to skipping of exon 13 and 14 (PMID: 9753072). The deleted region contains the NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) variant which has been classified by the SCID VCEP as VUS (PM4_supporting). This variant was identified in at least one T-B+ SCID patient in whom, IL-2-induced JAK3 phosphorylation showed that the JAK3 protein was only marginally activated, and IL-2-induced phosphorylation of STAT5B/A was not detected in BCLs from the patient. This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (PMID: 9753072; PP4_moderate). This patient (PMID: 9753072) was homozygous for the variant and two additional patients are compound heterozygous with second variants confirmed in trans (but not yet classified by the SCID-VCEP so considered VUS), Leu1017Pro (PMID: 33777394) and c.115dup (PMID: 21184155) for three patients in total with this variant (PM3). The highest population allele frequency in gnomAD v2.1.1 is 0.00001239 (1/80718 alleles in the European non-Finnish population), which is lower than the ClinGen SCID VCEP threshold of <0.000115 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3, PM4_supporting, PP4_moderate. (VCEP specifications version 1).

PM2_Supporting

The highest population allele frequency in gnomAD v2.1.1 is 0.00001239 (1/80718 alleles in the European non-Finnish population), which is lower than the ClinGen SCID VCEP threshold of <0.000115 (PM2_supporting).

PM4_Supporting

The apparent missense variant is observed in patient cDNA to cause an in-frame deletion of 213bp (71 amino acids; p.Ser568_Leu638del) due to skipping of exon 13 and 14. The resulting low-molecular weight protein was observed in equimolar amounts with normal-sized JAK3 by Western-blot analysis of patient BCL lysates (PMID: 9753072). The deleted region contains the NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) variant has been classified by the SCID VCEP as VUS, meeting the PM4_supporting requirements. Nine additional JAK3 VUS missense variants associated with T-B+ SCID in ClinVar are also within the deletion but have not been assessed by the SCID VCEP, a (likely) pathogenic classification could increase this to PM4 but would not impact the overall Likely Pathogenic classification of this Arg582Trp variant.

PM3

At least three SCID patients have been reported with this variant. One patient (PMID: 9753072) is homozygous (0.5pt). And two patients are compound heterozygous with second variants confirmed in trans but not yet classified by the SCID-VCEP so considered VUS, Leu1017Pro (PMID: 33777394; 0.25pt) and c.115dup (PMID: 21184155; 0.25pt). Total 1pt Classification of the in trans variants as Likely Pathogenic/Pathogenic could increase this to PM2_strong but would not impact the overall Likely Pathogenic classification of this Arg582Trp variant.

PP4_Moderate

This variant was identified in at least one T-B+ SCID (0.5pt) patient meeting diagnostic criteria (absent T cells, no CD3T cell counts provided but reported as T-, and unresponsive to stimulation with PHA 0.5pt?). Additionally, IL-2-induced JAK3 phosphorylation showed that the JAK3 protein was marginally activated (1pt) and IL-2-induced phosphorylation of STAT5B/A was not detected in BCLs from the patient (1pt). This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 2.5pt; PMID: 9753072; PP4_moderate).

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

The Arg582Gln occurs at the same amino acid residue and has been classified VUS by the SCID VCEP.

Curation History

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