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Variant: NM_000215.4(JAK3):c.678_679del (p.Cys227fs)

CA214096

36423 (ClinVar)

Gene: JAK3
Condition: T-B+ severe combined immunodeficiency due to JAK3 deficiency
Inheritance Mode: Autosomal recessive inheritance
UUID: b7631ff0-e33e-4d03-ba36-9006d218111e
Approved on: 2024-01-17
Published on: 2024-01-17

HGVS expressions

NM_000215.4:c.678_679del
NM_000215.4(JAK3):c.678_679del (p.Cys227fs)
NC_000019.10:g.17842498_17842499del
CM000681.2:g.17842498_17842499del
NC_000019.9:g.17953307_17953308del
CM000681.1:g.17953307_17953308del
NC_000019.8:g.17814307_17814308del
NG_007273.1:g.10493_10494del
ENST00000458235.7:c.678_679del
ENST00000458235.5:c.678_679del
ENST00000526008.5:n.778_779del
ENST00000527031.5:n.768_769del
ENST00000527670.5:c.678_679del
ENST00000528293.1:n.1109_1110del
ENST00000528705.1:n.27_28del
ENST00000534444.1:c.678_679del
NM_000215.3:c.678_679del
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Pathogenic

Met criteria codes 4
PM2_Supporting PP4 PVS1 PM3_Supporting

Evidence Links 0

Expert Panel

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 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).
Met criteria codes
PM2_Supporting
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).
PP4
Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total=1pt, PP4. (PMID: 23384681)
PVS1
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).
PM3_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.
Curation History
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