NM_000214.3(JAG1):c.601C>T (p.Arg201Cys) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Mar 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001175471.1

Allele description [Variation Report for NM_000214.3(JAG1):c.601C>T (p.Arg201Cys)]

NM_000214.3(JAG1):c.601C>T (p.Arg201Cys)

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.601C>T (p.Arg201Cys)
HGVS:
  • NC_000020.11:g.10658561G>A
  • NG_007496.1:g.20486C>T
  • NM_000214.3:c.601C>TMANE SELECT
  • NP_000205.1:p.Arg201Cys
  • LRG_1191t1:c.601C>T
  • LRG_1191:g.20486C>T
  • LRG_1191p1:p.Arg201Cys
  • NC_000020.10:g.10639209G>A
  • NM_000214.2:c.601C>T
Protein change:
R201C
Links:
dbSNP: rs794727618
NCBI 1000 Genomes Browser:
rs794727618
Molecular consequence:
  • NM_000214.3:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001339050Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 24, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.

Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, Redfield C, Baron M, Lea SM, Handford PA.

Nat Struct Mol Biol. 2008 Aug;15(8):849-57. doi: 10.1038/nsmb.1457. Epub 2008 Jul 27.

PubMed [citation]
PMID:
18660822
PMCID:
PMC2669539

An Atypical Presentation of Alagille Syndrome.

Wu KY, Treece AL, Russo PA, Wen JW.

Pediatr Dev Pathol. 2018 Jan-Feb;21(1):79-83. doi: 10.1177/1093526616686902. Epub 2017 Jan 25.

PubMed [citation]
PMID:
29187043

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339050.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: JAG1 c.601C>T (p.Arg201Cys) results in a non-conservative amino acid change located in the disulphide-rich Delta/Serrate/Lag-2 (DSL) protein domain (IPR001774 and Cordle_2008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.601C>T has been reported in the literature in at least one individual with an atypical presentation of Alagille syndrome (Wu_2018). These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a study investigated a different missense (Arg201Ala) affecting the same residue, and found a partial loss of function, for both in vitro Notch-binding and in vivo signaling in Drosophila (Cordle_2008). These data might support a functional role for the Arg 201 residue. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 10, 2021

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