NM_000214.3(JAG1):c.439+1G>A AND Alagille syndrome due to a JAG1 point mutation

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001853157.7

Allele description [Variation Report for NM_000214.3(JAG1):c.439+1G>A]

NM_000214.3(JAG1):c.439+1G>A

Gene:

JAG1:jagged canonical Notch ligand 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p12.2

Genomic location:

Preferred name:

NM_000214.3(JAG1):c.439+1G>A

HGVS:

NC_000020.11:g.10663962C>T
NG_007496.1:g.15085G>A
NM_000214.3:c.439+1G>AMANE SELECT
LRG_1191t1:c.439+1G>A
LRG_1191:g.15085G>A
NC_000020.10:g.10644610C>T
NM_000214.2:c.439+1G>A

Links:

dbSNP: rs863223648

NCBI 1000 Genomes Browser:

rs863223648

Molecular consequence:

NM_000214.3:c.439+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Alagille syndrome due to a JAG1 point mutation
Synonyms:: HEPATIC DUCTULAR HYPOPLASIA, SYNDROMATIC; Alagille Syndrome 1; JAG1-Related Alagille Syndrome
Identifiers:: MONDO: MONDO:0016862; MedGen: C1956125; Orphanet: 52; OMIM: 118450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002242883	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 11139247, 11180599, 29483232, 31343788, 28492532
SCV004847132	Genomic Medicine Lab, University of California San Francisco	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005068255	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2024)	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

SCV002242883

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 29, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004847132

Genomic Medicine Lab, University of California San Francisco

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

paternal

clinical testing

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

SCV005068255

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 1, 2024)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome.

Crosnier C, Driancourt C, Raynaud N, Hadchouel M, Meunier-Rotival M.

Hum Mutat. 2001;17(1):72-3.

PubMed [citation]

PMID:: 11139247

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002242883.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	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 Genomic Medicine Lab, University of California San Francisco, SCV004847132.1

#	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	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV005068255.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

ClinVar

Relating variation to medicine