NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 21, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001963164.7

Allele description [Variation Report for NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter)]

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

Gene:

JAK3:Janus kinase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.11

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000019.10:g.17834610G>A
NG_007273.1:g.18382C>T
NM_000215.4:c.2311C>TMANE SELECT
NP_000206.2:p.Arg771Ter
LRG_77:g.18382C>T
NC_000019.9:g.17945419G>A

Protein change:

R771*

Links:

dbSNP: rs1198251679

NCBI 1000 Genomes Browser:

rs1198251679

Molecular consequence:

NM_000215.4:c.2311C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: T-B+ severe combined immunodeficiency due to JAK3 deficiency
Synonyms:: SCID, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-NEGATIVE; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative; SCID, autosomal recessive, T-negative/B-positive type
Identifiers:: MONDO: MONDO:0010938; MedGen: C1833275; Orphanet: 35078; OMIM: 600802

Recent activity

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V5G20_RS18010 [Brevibacillus borstelensis]
V5G20_RS18010 [Brevibacillus borstelensis]
Gene ID:89500543

Gene
V5G20_RS22090 [Brevibacillus borstelensis]
V5G20_RS22090 [Brevibacillus borstelensis]
Gene ID:89501359

Gene
txid307632[Organism:noexp] (4)
Identical Protein Groups
prostaglandin E synthase 3 isoform X2 [Homo sapiens]
prostaglandin E synthase 3 isoform X2 [Homo sapiens]
gi|530399615|ref|XP_005268633.1|

Protein
prostaglandin E synthase 3 isoform a [Homo sapiens]
prostaglandin E synthase 3 isoform a [Homo sapiens]
gi|23308579|ref|NP_006592.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002243708	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7481768, 11668621, 28492532
SCV004809134	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications JAK3 V1.0.0)	Pathogenic (Feb 21, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002243708

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 28, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004809134

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications JAK3 V1.0.0)

Pathogenic
(Feb 21, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.

Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, O'Shea JJ, Leonard WJ.

Science. 1995 Nov 3;270(5237):797-800.

PubMed [citation]

PMID:: 7481768

Eleven novel JAK3 mutations in patients with severe combined immunodeficiency-including the first patients with mutations in the kinase domain.

Mella P, Schumacher RF, Cranston T, de Saint Basile G, Savoldi G, Notarangelo LD.

Hum Mutat. 2001 Oct;18(4):355-6.

PubMed [citation]

PMID:: 11668621

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243708.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1459771). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 11668621). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg771*) in the JAK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAK3 are known to be pathogenic (PMID: 7481768, 11668621).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004809134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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