NM_000215.4(JAK3):c.2291C>T (p.Pro764Leu) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:: Uncertain significance (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:: RCV001070458.8

Allele description [Variation Report for NM_000215.4(JAK3):c.2291C>T (p.Pro764Leu)]

NM_000215.4(JAK3):c.2291C>T (p.Pro764Leu)

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.2291C>T (p.Pro764Leu)

Other names:

NM_000215.4(JAK3):c.2291C>T; p.Pro764Leu

HGVS:

NC_000019.10:g.17834630G>A
NG_007273.1:g.18362C>T
NM_000215.4:c.2291C>TMANE SELECT
NP_000206.2:p.Pro764Leu
LRG_77t1:c.2291C>T
LRG_77:g.18362C>T
NC_000019.9:g.17945439G>A
NM_000215.3:c.2291C>T

Protein change:

P764L

Links:

dbSNP: rs149982493

NCBI 1000 Genomes Browser:

rs149982493

Molecular consequence:

NM_000215.4:c.2291C>T - 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
SCV001235690	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809133	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications JAK3 V1.0.0)	Uncertain significance (Feb 21, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001235690

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 27, 2021)

germline

clinical testing

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

SCV004809133

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications JAK3 V1.0.0)

Uncertain significance
(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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001235690.4

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

Description

This sequence change replaces proline with leucine at codon 764 of the JAK3 protein (p.Pro764Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs149982493, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004809133.1

#	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.2291C>T variant in JAK3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 764 (p.Pro764Leu). The filtering allele frequency (the upper threshold of the 95% CI of 3/33008) of the c.2291C>T variant is 0.00002408 for African/African American subpopulation chromosomes by gnomAD v.4.0.0, which is lower than the threshold (<0.000115) defined by the ClinGen Severe Combined immunodeficiency Disease Variant Curation Expert Panel (SCID VCEP) for JAK3 variants (PM2_supporting). One patient was found reported on Clinvar; however, the affected status is unknown (VCV000863482.6). This variant does not meet the criteria to be classified as pathogenic, likely pahogenic, benign or likely benign for T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID JAK3 VCEP (PM2_supporting) ; therefore is classified as a variant of unknown significance (VUS) for this disease. (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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