Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15712272, 10220506, 33142350, 24748328, 25676721, 12442286, 22488849, 9207788)
ClinVar Genomic variation as it relates to human health
NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs)
Germline
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.
(14)
Help
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.
Pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs)
Variation ID: 177941 Accession: VCV000177941.57
- Type and length
-
Microsatellite, 4 bp
- Location
-
Cytogenetic: 20p12.2 20: 10645245-10645248 (GRCh38) [ NCBI UCSC ] 20: 10625893-10625896 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 31, 2015 Oct 20, 2024 Mar 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000214.3:c.2122_2125del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000205.1:p.Gln708fs frameshift NC_000020.11:g.10645245ACTG[1] NC_000020.10:g.10625893ACTG[1] NG_007496.1:g.33795CAGT[1] LRG_1191:g.33795CAGT[1] LRG_1191t1:c.2122_2125del LRG_1191p1:p.Gln708fs - Protein change
- Q708fs
- Other names
- -
- Canonical SPDI
- NC_000020.11:10645244:ACTGACTG:ACTG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| JAG1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1839 | 1883 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000154602.22 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 7, 2024 | RCV000199484.35 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2011 | RCV000844632.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 14, 2019 | RCV001197474.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 9, 2018 | RCV001328149.8 | |
|
JAG1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 14, 2023 | RCV004551336.2 |
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. |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000250486.13
First in ClinVar: Oct 11, 2015 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15712272, 10220506, 33142350, 24748328, 25676721, 12442286, 22488849, 9207788) (less)
|
|
|
Pathogenic
(Feb 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001748016.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000707420.2
First in ClinVar: Oct 09, 2016 Last updated: Jun 04, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Mar 09, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital heart malformation
Arteriohepatic dysplasia
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204275.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a … (more)
The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a premature stop cod on 34 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein (loss of function). This variant has been reported in o ne child with Alagille syndrome as well as the mildly affected mother. Absence from 100 healthy control chromosomes supports a pathogenic role (Li 1997, varian t reported as 2531del4). In addition, it was reported as de novo in 5 additional , unrelated individuals with Alagille syndrome (Crosnier 1999 - variant reported as 2535-2538delCAGT). Loss of function is an established mechanism of disease f or the JAG1 gene and is typically associated with Alagille syndrome (GeneReviews ). In summary, the Gln708fs variant meets our criteria for pathogenicity (http:/ /pcpgm.partners.org/LMM) and is highly likely to be causative for disease. (less)
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tetralogy of Fallot
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368227.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
|
|
|
Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alagille syndrome due to a JAG1 point mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045968.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Low-set ears (present) , Hypoplastic aortic arch (present) , High forehead (present) , Retrognathia (present) , Elevated gamma-glutamyltransferase level (present)
|
|
|
Pathogenic
(Sep 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alagille syndrome due to a JAG1 point mutation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545815.8
First in ClinVar: Jan 31, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln708Valfs*34) in the JAG1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln708Valfs*34) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alagille syndrome (PMID: 9207788, 12442286, 15712272, 22488849, 25676721). This variant is also known as c.2531_2534delCAGT. ClinVar contains an entry for this variant (Variation ID: 177941). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alagille syndrome due to a JAG1 point mutation
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806224.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Nov 01, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Alagille syndrome due to a JAG1 point mutation
Affected status: yes
Allele origin:
de novo
|
Istanbul Faculty of Medicine, Istanbul University
Accession: SCV004023385.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Pathogenic
(Aug 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778280.1
First in ClinVar: Jun 04, 2018 Last updated: Jun 04, 2018 |
|
|
|
Pathogenic
(Nov 09, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Arteriohepatic dysplasia
Affected status: yes
Allele origin:
unknown
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449346.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is heterozygous for a 4bp deletion, c.2122_2125del, in the JAG1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Gln708Valfs*34) … (more)
This individual is heterozygous for a 4bp deletion, c.2122_2125del, in the JAG1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Gln708Valfs*34) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been previously reported in multiple patients with with Alagille syndrome (Jurkiewicz et al Hum Mutat. 2005 Mar;25(3):321 and also see ClinVar https://www.ncbi.nlm.nih.gov/clinvar/variation/177941/) . This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PP5). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951229.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965321.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Dec 14, 2023)
|
no assertion criteria provided
Method: clinical testing
|
JAG1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120662.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The JAG1 c.2122_2125delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Gln708Valfs*34). This variant has been reported to be causative for … (more)
The JAG1 c.2122_2125delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Gln708Valfs*34). This variant has been reported to be causative for Alagille syndrome (Li et al 1997. PubMed ID: 9207788; Jurkiewicz et al. 2005. PubMed ID: 15712272; Table 2, Qiao et al. 2021. PubMed ID: 33142350). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a premature stop cod on 34 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein (loss of function). This variant has been reported in o ne child with Alagille syndrome as well as the mildly affected mother. Absence from 100 healthy control chromosomes supports a pathogenic role (Li 1997, varian t reported as 2531del4). In addition, it was reported as de novo in 5 additional , unrelated individuals with Alagille syndrome (Crosnier 1999 - variant reported as 2535-2538delCAGT). Loss of function is an established mechanism of disease f or the JAG1 gene and is typically associated with Alagille syndrome (GeneReviews ). In summary, the Gln708fs variant meets our criteria for pathogenicity (http:/ /pcpgm.partners.org/LMM) and is highly likely to be causative for disease.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
This sequence change creates a premature translational stop signal (p.Gln708Valfs*34) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alagille syndrome (PMID: 9207788, 12442286, 15712272, 22488849, 25676721). This variant is also known as c.2531_2534delCAGT. ClinVar contains an entry for this variant (Variation ID: 177941). For these reasons, this variant has been classified as Pathogenic.
Comment:
This individual is heterozygous for a 4bp deletion, c.2122_2125del, in the JAG1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Gln708Valfs*34) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been previously reported in multiple patients with with Alagille syndrome (Jurkiewicz et al Hum Mutat. 2005 Mar;25(3):321 and also see ClinVar https://www.ncbi.nlm.nih.gov/clinvar/variation/177941/) . This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PP5).
Comment:
The JAG1 c.2122_2125delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Gln708Valfs*34). This variant has been reported to be causative for Alagille syndrome (Li et al 1997. PubMed ID: 9207788; Jurkiewicz et al. 2005. PubMed ID: 15712272; Table 2, Qiao et al. 2021. PubMed ID: 33142350). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15712272, 10220506, 33142350, 24748328, 25676721, 12442286, 22488849, 9207788)
Comment:
The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a premature stop cod on 34 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein (loss of function). This variant has been reported in o ne child with Alagille syndrome as well as the mildly affected mother. Absence from 100 healthy control chromosomes supports a pathogenic role (Li 1997, varian t reported as 2531del4). In addition, it was reported as de novo in 5 additional , unrelated individuals with Alagille syndrome (Crosnier 1999 - variant reported as 2535-2538delCAGT). Loss of function is an established mechanism of disease f or the JAG1 gene and is typically associated with Alagille syndrome (GeneReviews ). In summary, the Gln708fs variant meets our criteria for pathogenicity (http:/ /pcpgm.partners.org/LMM) and is highly likely to be causative for disease.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
This sequence change creates a premature translational stop signal (p.Gln708Valfs*34) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alagille syndrome (PMID: 9207788, 12442286, 15712272, 22488849, 25676721). This variant is also known as c.2531_2534delCAGT. ClinVar contains an entry for this variant (Variation ID: 177941). For these reasons, this variant has been classified as Pathogenic.
Comment:
This individual is heterozygous for a 4bp deletion, c.2122_2125del, in the JAG1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Gln708Valfs*34) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been previously reported in multiple patients with with Alagille syndrome (Jurkiewicz et al Hum Mutat. 2005 Mar;25(3):321 and also see ClinVar https://www.ncbi.nlm.nih.gov/clinvar/variation/177941/) . This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PP5).
Comment:
The JAG1 c.2122_2125delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Gln708Valfs*34). This variant has been reported to be causative for Alagille syndrome (Li et al 1997. PubMed ID: 9207788; Jurkiewicz et al. 2005. PubMed ID: 15712272; Table 2, Qiao et al. 2021. PubMed ID: 33142350). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants 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 |
|---|---|---|---|---|
| Clinical features, outcomes, and genetic analysis in Korean children with Alagille syndrome. | Cho JM | Pediatrics international : official journal of the Japan Pediatric Society | 2015 | PMID: 25676721 |
| Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features. | Lin HC | American journal of medical genetics. Part A | 2012 | PMID: 22488849 |
| Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients. | Jurkiewicz D | Human mutation | 2005 | PMID: 15712272 |
| DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients. | Heritage ML | Human mutation | 2002 | PMID: 12442286 |
| Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. | Colliton RP | Human mutation | 2001 | PMID: 11180599 |
| Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. | Crosnier C | Gastroenterology | 1999 | PMID: 10220506 |
| Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. | Li L | Nature genetics | 1997 | PMID: 9207788 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=JAG1 | - | - | - | - |
| - | - | - | - | DOI: 10.26650/IUITFD.1321220 |
Text-mined citations for rs727504412 ...
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 Nov 19, 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.