NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs) AND Alagille syndrome due to a JAG1 point mutation

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 25, 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:: RCV000154602.22

Allele description [Variation Report for NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs)]

NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

20p12.2

Genomic location:

Preferred name:

NM_000214.3(JAG1):c.2122_2125del (p.Gln708fs)

HGVS:

NC_000020.10:g.10625893_10625896del
NC_000020.11:g.10645245ACTG[1]
NG_007496.1:g.33795CAGT[1]
NM_000214.3:c.2122_2125delMANE SELECT
NP_000205.1:p.Gln708fs
LRG_1191t1:c.2122_2125del
LRG_1191:g.33795CAGT[1]
LRG_1191p1:p.Gln708fs
NC_000020.10:g.10625893ACTG[1]
NC_000020.10:g.10625893_10625896del
NC_000020.10:g.10625893_10625896delACTG
NM_000214.2:c.2122_2125del
p.Gln708ValfsX34
p.Q708Vfs*34

Protein change:

Q708fs

Links:

dbSNP: rs727504412

NCBI 1000 Genomes Browser:

rs727504412

Molecular consequence:

NM_000214.3:c.2122_2125del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000545815	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 29, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11180599, 9207788, 12442286, 15712272, 22488849, 25676721, 28492532
SCV004023385	Istanbul Faculty of Medicine, Istanbul University	no assertion criteria provided	Pathogenic (Nov 1, 2022)	de novo	clinical testing
SCV004045968	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Aug 16, 2023)	germline	clinical testing	Citation Link,
SCV004806224	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 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	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	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

Citations

PubMed

Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients.

Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, Spinner NB.

Hum Mutat. 2001 Feb;17(2):151-2.

PubMed [citation]

PMID:: 11180599

Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.

Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB.

Nat Genet. 1997 Jul;16(3):243-51.

PubMed [citation]

PMID:: 9207788

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545815.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	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 Istanbul Faculty of Medicine, Istanbul University, SCV004023385.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045968.1

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

#	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		1	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806224.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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