NM_000215.4(JAK3):c.2317G>A (p.Val773Ile) 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:: RCV001202151.7

Allele description [Variation Report for NM_000215.4(JAK3):c.2317G>A (p.Val773Ile)]

NM_000215.4(JAK3):c.2317G>A (p.Val773Ile)

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.2317G>A (p.Val773Ile)

Other names:

NM_000215.4(JAK3):c.2317G>A; p.Val773Ile

HGVS:

NC_000019.10:g.17834604C>T
NG_007273.1:g.18388G>A
NM_000215.4:c.2317G>AMANE SELECT
NP_000206.2:p.Val773Ile
LRG_77t1:c.2317G>A
LRG_77:g.18388G>A
NC_000019.9:g.17945413C>T
NM_000215.3:c.2317G>A

Protein change:

V773I

Links:

dbSNP: rs201531563

NCBI 1000 Genomes Browser:

rs201531563

Molecular consequence:

NM_000215.4:c.2317G>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
SCV001373255	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809135	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

SCV001373255

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 10, 2022)

germline

clinical testing

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

SCV004809135

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, SCV001373255.4

#	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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 773 of the JAK3 protein (p.Val773Ile). This variant is present in population databases (rs201531563, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 933853). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAK3 protein function. 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, SCV004809135.1

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

Description

NM_000215.4(JAK3):c.2317G>A variant in JAK3 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 773 (p.Val773Ile). The total Grpmax Filtering allele frequency (the upper threshold of the 95% confidence) is 0.00004416 for East Asian 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). This variant has been found in ClinVar; however, the affected status of the patient is unknown (VCV000933853.6) This variant does not meet the criteria to be classified as pathogenic, likely pathogenic, 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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