VCV000007620.15 - ClinVar

NM_000214.3(JAG1):c.551G>A (p.Arg184His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000214.3(JAG1):c.551G>A (p.Arg184His)

Variation ID: 7620 Accession: VCV000007620.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p12.2 20: 10658611 (GRCh38) [ NCBI UCSC ] 20: 10639259 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 6, 2017	Apr 6, 2024	Mar 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000214.3:c.551G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000205.1:p.Arg184His	missense
NC_000020.11:g.10658611C>T
NC_000020.10:g.10639259C>T
NG_007496.1:g.20436G>A
LRG_1191:g.20436G>A
LRG_1191t1:c.551G>A	LRG_1191p1:p.Arg184His
	P78504:p.Arg184His

... more HGVS ... less HGVS

Protein change

R184H

Other names

Canonical SPDI

NC_000020.11:10658610:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA254223 UniProtKB: P78504#VAR_013194 OMIM: 601920.0006 dbSNP: rs121918351 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
JAG1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1843	1887

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Alagille syndrome due to a JAG1 point mutation	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 29, 2024	RCV000008059.24
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 7, 2017	RCV000725979.11
Alagille syndrome due to a JAG1 point mutation Charcot-Marie-Tooth disease, axonal, Type 2HH Deafness, congenital heart defects, and posterior embryotoxon Tetralogy of Fallot	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2021	RCV002476943.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 07, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340966.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 11157803‚ 22487239‚ 9585603 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=JAG1 Number of individuals with the variant: 4 Sex: mixed
Pathogenic (Jul 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alagille syndrome due to a JAG1 point mutation Tetralogy of Fallot Deafness, congenital heart defects, and posterior embryotoxon Charcot-Marie-Tooth disease, axonal, Type 2HH Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894216.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alagille syndrome due to a JAG1 point mutation Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807839.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alagille syndrome due to a JAG1 point mutation Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002102428.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022	Comment: _x000D_ Criteria applied: PS3, PM5_STR, PS4_MOD, PM2_SUP, PP2, PP3
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alagille syndrome due to a JAG1 point mutation Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000829372.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 10220506‚ 10533065‚ 11058898‚ 22487239‚ 9585603‚ 12442286‚ 24748328‚ 25676721 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this residue have been observed in individuals with JAG1-related conditions (PMID: 10220506, 10533065), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects JAG1 function (PMID: 11058898, 22487239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt JAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 7620). This missense change has been observed in individuals with Alagille syndrome (PMID: 9585603, 10220506, 12442286, 24748328, 25676721). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 184 of the JAG1 protein (p.Arg184His). (less)
Pathogenic (Feb 15, 2001)	no assertion criteria provided Method: literature only	ALAGILLE SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028264.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017	Publications: PubMed (2) PubMed: 9585603‚ 11157803 Comment on evidence: See 601920.0005 and Krantz et al. (1998). In 2 assays of JAG1 function, Morrissette et al. (2001) found that the R184H mutation was associated with … (more) See 601920.0005 and Krantz et al. (1998). In 2 assays of JAG1 function, Morrissette et al. (2001) found that the R184H mutation was associated with loss of Notch signaling activity relative to wildtype JAG1. The protein containing the R184H substitution was not present on the cell surface, was abnormally glycosylated, and appeared to be abnormally accumulated, possibly in the endoplasmic reticulum. (less)
not provided (-)	no classification provided Method: literature only	Alagille syndrome due to a JAG1 point mutation Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001167335.2 First in ClinVar: Mar 09, 2020 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301450 BookShelf: NBK1273 BookShelf: NBK1273

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this residue have been observed in individuals with JAG1-related conditions (PMID: 10220506, 10533065), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects JAG1 function (PMID: 11058898, 22487239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt JAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 7620). This missense change has been observed in individuals with Alagille syndrome (PMID: 9585603, 10220506, 12442286, 24748328, 25676721). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 184 of the JAG1 protein (p.Arg184His).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alagille Syndrome.	Adam MP	-	2024	PMID: 20301450
Clinical features, outcomes, and genetic analysis in Korean children with Alagille syndrome.	Cho JM	Pediatrics international : official journal of the Japan Pediatric Society	2015	PMID: 25676721
Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome.	Jurkiewicz D	Journal of applied genetics	2014	PMID: 24748328
Functional analysis of the Notch ligand Jagged1 missense mutant proteins underlying Alagille syndrome.	Tada M	The FEBS journal	2012	PMID: 22487239
DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients.	Heritage ML	Human mutation	2002	PMID: 12442286
Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.	Morrissette JD	Human molecular genetics	2001	PMID: 11157803
Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population.	Heritage ML	Human mutation	2000	PMID: 11058898
Jagged-1 mutation analysis in Italian Alagille syndrome patients.	Pilia G	Human mutation	1999	PMID: 10533065
Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome.	Crosnier C	Gastroenterology	1999	PMID: 10220506
Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.	Krantz ID	American journal of human genetics	1998	PMID: 9585603
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=JAG1	-	-	-	-
click to load more click to collapse

Text-mined citations for rs121918351 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000214.3(JAG1):c.551G>A (p.Arg184His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918351 ...