ClinVar Genomic variation as it relates to human health
NM_000215.4(JAK3):c.678_679del (p.Cys227fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000215.4(JAK3):c.678_679del (p.Cys227fs)
Variation ID: 36423 Accession: VCV000036423.8
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 19p13.11 19: 17842498-17842499 (GRCh38) [ NCBI UCSC ] 19: 17953307-17953308 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000215.4:c.678_679del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000206.2:p.Cys227fs frameshift NM_000215.3:c.678_679delCT NC_000019.10:g.17842498_17842499del NC_000019.9:g.17953307_17953308del NG_007273.1:g.10493_10494del LRG_77:g.10493_10494del - Protein change
- Other names
- NM_000215.4(JAK3):c.678_679del
- p.Cys227fs
- Canonical SPDI
- NC_000019.10:17842497:AG:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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JAK3 | - | - |
GRCh38 GRCh37 |
1223 | 1236 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2011 | RCV000030095.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 21, 2018 | RCV000255037.2 | |
Pathogenic (4) |
reviewed by expert panel
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Nov 14, 2023 | RCV002051797.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 14, 2023)
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reviewed by expert panel
Method: curation
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Accession: SCV004102774.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The c.678_679del (p.Cys227ProfsTer?) (NM_000215.4) variant in JAK3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/24 leading to nonsense mediated … (more)
The c.678_679del (p.Cys227ProfsTer?) (NM_000215.4) variant in JAK3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003577 (1/27956) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, meeting this criterion (PM2_Supporting). One patient compound heterozygous with variant c.1767C>T (PMID: 23384681). It was not evaluated at this moment because the pathogenic level was already reached. One homozygous patient described on ClinVar (3billion, T-B+ severe combined immunodeficiency due to JAK3 deficiency) affected status: yes. Hepatosplenomegaly (present), Pneumonia (present) - (0.5pt). PM3_Supporting. Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total=1pt, PP4. (PMID: 23384681). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PP4, PM2_supporting and PM3_supporting. (VCEP specifications version 1). (less)
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Pathogenic
(Aug 23, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321791.7
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
The c.678_679delCT pathogenic variant in the JAK3 gene has been reported previously in association with SCID (Cattaneo et al., 2013). The deletion causes a frameshift … (more)
The c.678_679delCT pathogenic variant in the JAK3 gene has been reported previously in association with SCID (Cattaneo et al., 2013). The deletion causes a frameshift starting with codon Cysteine 227, changes this amino acid to a Proline residue and creates a premature Stop codon at position 49 of the new reading frame, denoted p.Cys227ProfsX49. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, the variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider this variant to be pathogenic. (less)
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Pathogenic
(Mar 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927605.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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likely pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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SCID
(autosomal unknown)
Affected status: yes, unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052750.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 28, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Observation 1:
Tissue: Blood
Observation 2:
Tissue: Blood
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318887.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more)
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 23384681). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000047). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hepatosplenomegaly (present) , Pneumonia (present)
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: research
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: yes
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924318.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297957.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys227Profs*49) in the JAK3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys227Profs*49) in the JAK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAK3 are known to be pathogenic (PMID: 7481768, 11668621). This variant is present in population databases (rs193922364, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 23384681, 34173127). ClinVar contains an entry for this variant (Variation ID: 36423). For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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SARS-CoV-2-Related Acute Respiratory Distress Syndrome Uncovers a Patient with Severe Combined Immunodeficiency Disease. | Al-Saud B | Journal of clinical immunology | 2021 | PMID: 34173127 |
Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment. | Cattaneo F | The Journal of allergy and clinical immunology | 2013 | PMID: 23384681 |
Eleven novel JAK3 mutations in patients with severe combined immunodeficiency-including the first patients with mutations in the kinase domain. | Mella P | Human mutation | 2001 | PMID: 11668621 |
Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. | Russell SM | Science (New York, N.Y.) | 1995 | PMID: 7481768 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b7631ff0-e33e-4d03-ba36-9006d218111e | - | - | - | - |
Text-mined citations for rs193922364 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.