ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.601C>T (p.Arg201Cys) (rs794727618)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178063 SCV000230050 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Invitae RCV000697814 SCV000826445 uncertain significance Alagille syndrome 1 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 201 of the JAG1 protein (p.Arg201Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with JAG1-related disease. ClinVar contains an entry for this variant (Variation ID: 197123). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CeGaT Praxis fuer Humangenetik 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.

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