NM_000214.3(JAG1):c.439C>T (p.Gln147Ter) AND Alagille syndrome due to a JAG1 point mutation

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 26, 2022
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:: RCV000370816.9

Allele description [Variation Report for NM_000214.3(JAG1):c.439C>T (p.Gln147Ter)]

NM_000214.3(JAG1):c.439C>T (p.Gln147Ter)

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.439C>T (p.Gln147Ter)

Other names:

Protein jagged-1

HGVS:

NC_000020.11:g.10663963G>A
NG_007496.1:g.15084C>T
NM_000214.3:c.439C>TMANE SELECT
NP_000205.1:p.Gln147Ter
LRG_1191t1:c.439C>T
LRG_1191:g.15084C>T
LRG_1191p1:p.Gln147Ter
NC_000020.10:g.10644611G>A
NM_000214.2:c.439C>T

Protein change:

Q147*

Links:

dbSNP: rs886043606

NCBI 1000 Genomes Browser:

rs886043606

Molecular consequence:

NM_000214.3:c.439C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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
SCV000645533	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 26, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16575836, 19948535, 26076142, 11180599, 28492532
SCV002050688	Credence Genomics	no assertion criteria provided	Pathogenic (Dec 20, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16575836, 26076142

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645533

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 26, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002050688

Credence Genomics

no assertion criteria provided

Pathogenic
(Dec 20, 2021)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Sri Lankan	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A.

J Med Genet. 2010 May;47(5):321-31. doi: 10.1136/jmg.2009.070391. Epub 2009 Nov 30.

PubMed [citation]

PMID:: 19948535

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 (5)

Details of each submission

From Invitae, SCV000645533.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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: 287254). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 16575836, 19948535, 26076142). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln147*) 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

From Credence Genomics, SCV002050688.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Sri Lankan	1	not provided	not provided	clinical testing	PubMed (2)

Description

This mutation caused stop gain in JAG1 gene and expected to result a pathogenic loss of function variant. This is previously reported by Warthen 2006 and Liting Li 2015 .

#	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

Last Updated: Mar 30, 2024

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