NM_000214.3(JAG1):c.693_694del (p.Arg231fs) AND Alagille syndrome due to a JAG1 point mutation

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000008056.12

Allele description [Variation Report for NM_000214.3(JAG1):c.693_694del (p.Arg231fs)]

NM_000214.3(JAG1):c.693_694del (p.Arg231fs)

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.693_694del (p.Arg231fs)

HGVS:

NC_000020.11:g.10658468CT[1]
NG_007496.1:g.20576AG[1]
NG_007496.1:g.20578_20579del
NM_000214.3:c.693_694delMANE SELECT
NP_000205.1:p.Arg231fs
LRG_1191t1:c.693_694del
LRG_1191:g.20576AG[1]
LRG_1191p1:p.Arg231fs
NC_000020.10:g.10639116CT[1]
NC_000020.10:g.10639116_10639117del
NC_000020.11:g.10658468_10658469del
NG_007496.1:g.20578_20579del
NM_000214.2:c.693_694delAG

Note:

NCBI staff standardized reporting of the location of this deletion from review of the trace in Figure 6 in the paper by Li et al.,1997 (PubMed 9207788).

Protein change:

R231fs

Links:

OMIM: 601920.0003; dbSNP: rs876660978

NCBI 1000 Genomes Browser:

rs876660978

Molecular consequence:

NM_000214.3:c.693_694del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000028261	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004298041	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9207788, 11180599, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000028261

OMIM

no assertion criteria provided

Pathogenic
(Jul 1, 1997)

germline

literature only

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

SCV004298041

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000028261.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with Alagille syndrome (118450), Li et al. (1997) demonstrated deletion of 2 bp at positions 1104 and 1105 of the JAG1 gene. The deletion was located within exon 4, adjacent to the splice donor site. The deletion led to a shift in reading frame and premature termination codon at residue 240 (deleting 979 residues of the protein). Two affected brothers in this family had liver disease, heart disease (valvular and peripheral pulmonic stenosis), posterior embryotoxon, and 'Alagille facies.' Their less severely affected mother had a heart murmur, posterior embryotoxon, and Alagille facies.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298041.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 7617). This variant is also known as 1104delAG. This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 9207788). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg231Serfs*10) 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).

#	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 3, 2024

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