This sequence change affects a donor splice site in intron 3 of the JAG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Alagille syndrome (PMID: 11139247, 11180599, 29483232, 31343788). ClinVar contains an entry for this variant (Variation ID: 213529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000214.3(JAG1):c.439+1G>A
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
5 out of 7 submissions contributed to this classification
Help
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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000214.3(JAG1):c.439+1G>A
Variation ID: 213529 Accession: VCV000213529.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p12.2 20: 10663962 (GRCh38) [ NCBI UCSC ] 20: 10644610 (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 May 29, 2016 Jul 5, 2025 Jun 30, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000214.3:c.439+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000020.11:g.10663962C>T NC_000020.10:g.10644610C>T NG_007496.1:g.15085G>A LRG_1191:g.15085G>A LRG_1191t1:c.439+1G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000020.11:10663961:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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| JAG1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2580 | 2626 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 30, 2025 | RCV000199991.7 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Feb 26, 2018 | RCV000845195.1 | |
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JAG1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 9, 2024 | RCV004553065.2 |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2024 | RCV001853157.7 |
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
Help
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. |
Expand all rows
Collapse all rows
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 29, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alagille syndrome due to a JAG1 point mutation |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002242883.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change affects a donor splice site in intron 3 of the JAG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Alagille syndrome (PMID: 11139247, 11180599, 29483232, 31343788). ClinVar contains an entry for this variant (Variation ID: 213529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Mar 23, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000707317.3
First in ClinVar: May 29, 2016 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
Sex: mixed
|
|
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Pathogenic
(Jun 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000250455.14
First in ClinVar: Oct 11, 2015 Last updated: Jul 05, 2025 |
Comment:
show
Canonical splice site variant predicted to result in protein truncation for which loss of function is a known mechanism of disease (PMID: 12442286); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11139247, 29483232, 24748328, 34185059, 28695677, 11180599, 11139239, 26076142, 31343788, Kanwar[CaseReport]2021, 36514505, 37511516, 37314652, 12442286) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Feb 23, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alagille syndrome due to a JAG1 point mutation |
Genomic Medicine Lab, University of California San Francisco
Accession: SCV004847132.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: paternal
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: paternal
Affected status: yes
|
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Pathogenic
(Jul 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alagille syndrome due to a JAG1 point mutation
(Autosomal dominant inheritance)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005068255.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Cholestasis (present) , Intrahepatic cholestasis (present) , Cholestatic liver disease (present)
|
|
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Likely pathogenic
(Feb 26, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Midaortic syndrome |
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000987131.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: yes
Zygosity: Single Heterozygote
|
|
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Pathogenic
(Feb 09, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
JAG1-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117208.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
show
The JAG1 c.439+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with Alagille syndrome (Table 1, Crosnier et al. 2000. PubMed ID: 11139247; Table 1, Jurkiewicz et al. 2014. PubMed ID: 24748328; Ohashi et al. 2017. PubMed ID: 28695677), as well as an individual with midaortic syndrome (Table 1, Warejko et al. 2018. PubMed ID: 29483232). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
Canonical splice site variant predicted to result in protein truncation for which loss of function is a known mechanism of disease (PMID: 12442286); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11139247, 29483232, 24748328, 34185059, 28695677, 11180599, 11139239, 26076142, 31343788, Kanwar[CaseReport]2021, 36514505, 37511516, 37314652, 12442286)
Comment:
The JAG1 c.439+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with Alagille syndrome (Table 1, Crosnier et al. 2000. PubMed ID: 11139247; Table 1, Jurkiewicz et al. 2014. PubMed ID: 24748328; Ohashi et al. 2017. PubMed ID: 28695677), as well as an individual with midaortic syndrome (Table 1, Warejko et al. 2018. PubMed ID: 29483232). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. | Gilbert MA | Human mutation | 2019 | PMID: 31343788 |
| Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome. | Warejko JK | Hypertension (Dallas, Tex. : 1979) | 2018 | PMID: 29483232 |
| Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome. | Jurkiewicz D | Journal of applied genetics | 2014 | PMID: 24748328 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. | Colliton RP | Human mutation | 2001 | PMID: 11180599 |
| Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. | Crosnier C | Human mutation | 2001 | PMID: 11139247 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=JAG1 | - | - | - | - |
Text-mined citations for rs863223648 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jul 05, 2025
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.