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NM_000215.4(JAK3):c.1503G>T (p.Gln501His) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 4, 2022
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:
RCV001204387.8

Allele description [Variation Report for NM_000215.4(JAK3):c.1503G>T (p.Gln501His)]

NM_000215.4(JAK3):c.1503G>T (p.Gln501His)

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.1503G>T (p.Gln501His)
HGVS:
  • NC_000019.10:g.17838329C>A
  • NG_007273.1:g.14663G>T
  • NM_000215.4:c.1503G>TMANE SELECT
  • NP_000206.2:p.Gln501His
  • NP_000206.2:p.Gln501His
  • LRG_77t1:c.1503G>T
  • LRG_77:g.14663G>T
  • LRG_77p1:p.Gln501His
  • NC_000019.9:g.17949138C>A
  • NM_000215.3:c.1503G>T
Protein change:
Q501H
Links:
dbSNP: rs201283129
NCBI 1000 Genomes Browser:
rs201283129
Molecular consequence:
  • NM_000215.4:c.1503G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001375592Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(May 4, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome.

Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E.

Br J Haematol. 2008 May;141(5):681-8. doi: 10.1111/j.1365-2141.2008.07081.x. Epub 2008 Apr 7.

PubMed [citation]
PMID:
18397343

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, SCV001375592.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 501 of the JAK3 protein (p.Gln501His). This variant is present in population databases (rs201283129, 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: 376114). 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. Experimental studies have shown that this missense change affects JAK3 function (PMID: 18397343). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024