NM_000215.4(JAK3):c.507C>A (p.Asp169Glu) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000009959.5

Allele description [Variation Report for NM_000215.4(JAK3):c.507C>A (p.Asp169Glu)]

NM_000215.4(JAK3):c.507C>A (p.Asp169Glu)

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.507C>A (p.Asp169Glu)

HGVS:

NC_000019.10:g.17843086G>T
NG_007273.1:g.9906C>A
NM_000215.4:c.507C>AMANE SELECT
NP_000206.2:p.Asp169Glu
NP_000206.2:p.Asp169Glu
LRG_77t1:c.507C>A
LRG_77:g.9906C>A
LRG_77p1:p.Asp169Glu
NC_000019.9:g.17953895G>T
NM_000215.3:c.507C>A

Note:

ClinGen staff contributed the HGVS expression for this variant.

Protein change:

D169E; ASP169GLU

Links:

OMIM: 600173.0006; dbSNP: rs147181709

NCBI 1000 Genomes Browser:

rs147181709

Molecular consequence:

NM_000215.4:c.507C>A - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030180	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004298113	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14615376, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000030180

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004298113

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases.

Zhou YJ, Chen M, Cusack NA, Kimmel LH, Magnuson KS, Boyd JG, Lin W, Roberts JL, Lengi A, Buckley RH, Geahlen RL, Candotti F, Gadina M, Changelian PS, O'Shea JJ.

Mol Cell. 2001 Nov;8(5):959-69.

PubMed [citation]

PMID:: 11741532

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.

Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O'Shea JJ, Buckley RH.

Blood. 2004 Mar 15;103(6):2009-18. Epub 2003 Nov 13.

PubMed [citation]

PMID:: 14615376

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000030180.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with T-, B+, NK- SCID (600802), Zhou et al. (2001) identified compound heterozygosity for 2 mutations in the JAK3 gene: an asp169-to-glu (D169E) substitution and a deletion of ala58 (600173.0007).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298113.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 169 of the JAK3 protein (p.Asp169Glu). This variant is present in population databases (rs147181709, gnomAD 0.002%). This missense change has been observed in individual(s) with JAK3-related conditions (PMID: 14615376). ClinVar contains an entry for this variant (Variation ID: 9365). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects JAK3 function (PMID: 14615376). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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