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]

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Variant: NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter)

CA404767321

1459771 (ClinVar)

Gene: JAK3

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

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 71da273a-1c14-414c-bbaf-e6aab89c6aae

Approved on: 2024-02-21

Published on: 2024-02-21

HGVS expressions

NM_000215.4:c.2311C>T

NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter)

NC_000019.10:g.17834610G>A

CM000681.2:g.17834610G>A

NC_000019.9:g.17945419G>A

CM000681.1:g.17945419G>A

NC_000019.8:g.17806419G>A

NG_007273.1:g.18382C>T

ENST00000526008.6:c.*868C>T

ENST00000696967.1:n.1488C>T

ENST00000696970.1:n.966C>T

ENST00000458235.7:c.2311C>T

ENST00000458235.5:c.2311C>T

ENST00000527031.5:n.2278+2117C>T

ENST00000527670.5:c.2311C>T

ENST00000534444.1:c.2311C>T

NM_000215.3:c.2311C>T

Pathogenic

PM2_Supporting PP4 PM3 PVS1

BS2 BS1 PS1 PM5 BA1

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.2311C>T (p.Arg771Ter) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The Filtering allele frequency (the upper threshold of the 95% confidence of 16/1111980) is 0.00001439 for European (non-Finnish) chromosomes by gnomeAD v 4.0.0, which is lower than the ClinGen SCID JAK3 VCEP threshold [(<0,000115)] for PM2_Supporting, and therefore meets this criterion (PM2_Supporting) At least one patient with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and *T-B+NK- lymphocyte subset profile (0.5pt), totalizing 1 points, which is highly specific for SCID (PP4) (PMID: 32445296). In addition, this variant has been detected in at least two individuals with SCID, in the homozygous state (PMID: 11668610, 32445296) (total points= 1.0 pt) (PM3). One additional patient was found on Clinvar; however, the affected status is unknown (VCV001459771.4) 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. (VCEP specifications version 1).

PM2_Supporting

The Filtering allele frequency (the upper threshold of the 95% confidence of 16/1111980) is 0.00001439 for European (non-Finnish) chromosomes by gnomeAD v 4.0.0, which is lower than the ClinGen SCID JAK3 VCEP threshold [(<0,000115)] for PM2_Supporting, and therefore meets this criterion (PM2_Supporting)

PP4

At least one patient (PMID: 32445296) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) and *T-B+NK- lymphocyte subset profile (0.5pt). (1 pts) (PP4)

PM3

This variant has been detected in at least two individual with SCID, in the homozygous state (PMID: 11668610, 32445296) (total points= 1.0 pt) (PM3)

PVS1

The NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. (PVS1).

BS2

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

BS1

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

PS1

Not missense

PM5

Not missense

BA1

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

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