ClinVar Miner

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

dbSNP: rs794727618
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000178063 SCV000230050 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Invitae RCV000697814 SCV000826445 uncertain significance Alagille syndrome due to a JAG1 point mutation 2023-05-01 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 197123). This missense change has been observed in individual(s) with Alagille syndrome (PMID: 29187043). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the JAG1 protein (p.Arg201Cys).
CeGaT Center for Human Genetics Tuebingen RCV000178063 SCV001247224 likely pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175471 SCV001339050 uncertain significance not specified 2020-03-24 criteria provided, single submitter clinical testing 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.
Preventiongenetics, part of Exact Sciences RCV003407657 SCV004106677 uncertain significance JAG1-related condition 2022-11-02 criteria provided, single submitter clinical testing The JAG1 c.601C>T variant is predicted to result in the amino acid substitution p.Arg201Cys. This variant was reported in an individual with atypical clinical and histopathologic presentation of Alagille syndrome (Wu et al. 2018. PubMed ID: 29187043). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, functional studies in a fruit fly model showed that a similar variant p.Arg201Ala could impact normal protein function (Cordle et al. 2008. PubMed ID: 18660822). Although we suspect that the c.601C>T (p.Arg201Cys) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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