NM_000215.4(JAK3):c.2062A>T (p.Ile688Phe) AND T-B+ severe combined immunodeficiency due to JAK3 deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 15, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000335092.18

Allele description [Variation Report for NM_000215.4(JAK3):c.2062A>T (p.Ile688Phe)]

NM_000215.4(JAK3):c.2062A>T (p.Ile688Phe)

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.2062A>T (p.Ile688Phe)

HGVS:

NC_000019.10:g.17834989T>A
NG_007273.1:g.18003A>T
NM_000215.4:c.2062A>TMANE SELECT
NP_000206.2:p.Ile688Phe
NP_000206.2:p.Ile688Phe
LRG_77t1:c.2062A>T
LRG_77:g.18003A>T
LRG_77p1:p.Ile688Phe
NC_000019.9:g.17945798T>A
NM_000215.3:c.2062A>T
P52333:p.Ile688Phe

Protein change:

I688F

Links:

UniProtKB: P52333#VAR_041726; dbSNP: rs35785705

NCBI 1000 Genomes Browser:

rs35785705

Molecular consequence:

NM_000215.4:c.2062A>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
SCV000411108	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV001671132	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000411108

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV001671132

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Dec 15, 2021)

germline

clinical testing

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

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

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 Illumina Laboratory Services, Illumina, SCV000411108.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Invitae, SCV001671132.3

#	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

Last Updated: Sep 16, 2024

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