NM_000214.3(JAG1):c.701G>A (p.Cys234Tyr) AND Deafness, congenital heart defects, and posterior embryotoxon

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 15, 2018
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:: RCV000008065.8

Allele description [Variation Report for NM_000214.3(JAG1):c.701G>A (p.Cys234Tyr)]

NM_000214.3(JAG1):c.701G>A (p.Cys234Tyr)

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.701G>A (p.Cys234Tyr)

HGVS:

NC_000020.11:g.10656452C>T
NG_007496.1:g.22595G>A
NM_000214.3:c.701G>AMANE SELECT
NP_000205.1:p.Cys234Tyr
LRG_1191t1:c.701G>A
LRG_1191:g.22595G>A
LRG_1191p1:p.Cys234Tyr
NC_000020.10:g.10637100C>T
P78504:p.Cys234Tyr

Protein change:

C234Y; CYS234TYR

Links:

UniProtKB: P78504#VAR_026318; OMIM: 601920.0012; dbSNP: rs121918353

NCBI 1000 Genomes Browser:

rs121918353

Molecular consequence:

NM_000214.3:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deafness, congenital heart defects, and posterior embryotoxon (DCHE)
Identifiers:: MONDO: MONDO:0060713; MedGen: C1866053; OMIM: 617992

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lysozyme-like protein 6 precursor [Homo sapiens]
lysozyme-like protein 6 precursor [Homo sapiens]
gi|317008577|ref|NP_001186880.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028270	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12022040, 20437614
SCV000883297	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 15, 2018)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 20437614, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000028270

OMIM

no assertion criteria provided

Pathogenic
(Jul 1, 2002)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000883297

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 15, 2018)

unknown

curation

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.

Le Caignec C, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, Moisan JP.

Am J Hum Genet. 2002 Jul;71(1):180-6. Epub 2002 May 17.

PubMed [citation]

PMID:: 12022040
PMCID:: PMC384977

Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.

Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJ, Woyciechowski S, Garbarini J, Loomes KM, Krantz ID, Urban Z, Gelb BD, Goldmuntz E, Spinner NB.

Hum Mutat. 2010 May;31(5):594-601. doi: 10.1002/humu.21231.

PubMed [citation]

PMID:: 20437614
PMCID:: PMC2914103

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000028270.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 7 affected members of a large family with mild to severe combined deafness, congenital heart defects, and posterior embryotoxon (DCHE; 617992) segregating as an autosomal dominant disorder, Le Caignec et al. (2002) detected heterozygosity for a G-to-A transition at nucleotide 701 in exon 5 of the JAG1 gene, resulting in a cys234-to-tyr (C234Y) substitution in the first epidermal growth factor (EGF)-like repeat domain. The mutation was not found in 7 unaffected family members or in 120 chromosomes from unrelated and unaffected individuals.

Bauer et al. (2010) investigated the functional significance of the C234Y variant. The C234Y mutant protein was sensitive to endoglycosidase H, suggesting that it is improperly posttranslationally modified. Whereas wildtype JAG1 is localized to the cell surface, trypsin degradation analysis and immunofluorescence showed no cell surface expression of C234Y mutant protein, consistent with its being retained intracellularly. Luciferase reporter assays showed that the C234Y mutant was unable to activate Notch signaling. Bauer et al. (2010) noted that residue 234 is located in the first EGF repeat of the JAG1 protein, in a region shown to be crucial for receptor-ligand interactions.

#	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 SIB Swiss Institute of Bioinformatics, SCV000883297.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as Likely Pathogenic, for Deafness, congenital heart defects, and posterior embryotoxon, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1-Moderate => PP1 upgraded in strength to Moderate . PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/20437614). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

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

Last Updated: Apr 23, 2022

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