NM_000215.4(JAK3):c.394C>A (p.Pro132Thr) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:: Benign (4 submissions)
Last evaluated:: Jan 23, 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:: RCV000550265.16

Allele description [Variation Report for NM_000215.4(JAK3):c.394C>A (p.Pro132Thr)]

NM_000215.4(JAK3):c.394C>A (p.Pro132Thr)

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.394C>A (p.Pro132Thr)

Other names:

p.P132T:CCA>ACA; NM_000215.4(JAK3):c.394C>A

HGVS:

NC_000019.10:g.17843406G>T
NG_007273.1:g.9586C>A
NM_000215.4:c.394C>AMANE SELECT
NP_000206.2:p.Pro132Thr
NP_000206.2:p.Pro132Thr
LRG_77t1:c.394C>A
LRG_77:g.9586C>A
LRG_77p1:p.Pro132Thr
NC_000019.9:g.17954215G>T
NM_000215.3:c.394C>A
P52333:p.Pro132Thr

Protein change:

P132T

Links:

UniProtKB: P52333#VAR_019336; dbSNP: rs3212723

NCBI 1000 Genomes Browser:

rs3212723

Molecular consequence:

NM_000215.4:c.394C>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
SCV000411124	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Apr 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24728327, 21599579, 18270328, 21821710, 20132407 Citation Link,
SCV000638326	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002803176	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jul 29, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242258	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications JAK3 V1.0.0)	Benign (Jan 23, 2024)	germline	curation	Citation Link

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Summary from all submissions

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

Citations

PubMed

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects.

Riera L, Lasorsa E, Bonello L, Sismondi F, Tondat F, Di Bello C, Di Celle PF, Chiarle R, Godio L, Pich A, Facchetti F, Ponzoni M, Marmont F, Zanon C, Bardelli A, Inghirami G.

Leuk Lymphoma. 2011 Sep;52(9):1742-50. doi: 10.3109/10428194.2011.574757. Epub 2011 May 23.

PubMed [citation]

PMID:: 21599579

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000411124.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000638326.6

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

From Fulgent Genetics, Fulgent Genetics, SCV002803176.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV004242258.1

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

Description

The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr). The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0).

#	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: Oct 8, 2024

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