ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.550C>T (p.Arg184Cys)

dbSNP: rs121918350
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000729764 SCV000857452 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing
Invitae RCV000008058 SCV003443368 pathogenic Alagille syndrome due to a JAG1 point mutation 2023-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the JAG1 protein (p.Arg184Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alagille syndrome (PMID: 9585603, 22405927). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7619). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on JAG1 protein function. This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10220506, 10533065, 22487239, 24748328). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000008058 SCV004046935 pathogenic Alagille syndrome due to a JAG1 point mutation criteria provided, single submitter clinical testing The missense variant c.550C>T (p.Arg184Cys) in JAG1 gene has been reported in affected individuals in the literature (Crosnier C et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg184Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 184 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg184Cys in JAG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
OMIM RCV000008058 SCV000028263 pathogenic Alagille syndrome due to a JAG1 point mutation 1998-06-01 no assertion criteria provided literature only

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