ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 386 of the JAG1 protein (p.Gly386Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alagille syndrome (PMID: 11058898, 22405927, 22488849, 24748328, 26076142). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213531). 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. Experimental studies have shown that this missense change does not substantially affect JAG1 function (PMID: 22487239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The missense variant c.1156G>A (p.Gly386Arg) in JAG1 gene has been reported in heterozygous state to be de novo in several individuals affected with Alagille syndrome (Lin HC et al.). Experimental studies have shown that this missense change has no impact on protein processing, subcellular localization or protein transactivation in vitro (Tada M et al.). The p.Gly386Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This sequence change replaces glycine with arginine at codon 386 of the JAG1 protein (p.Gly386Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. The amino acid change p.Gly386Arg in JAG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

The JAG1 c.1156G>A variant is predicted to result in the amino acid substitution p.Gly386Arg. This variant has been reported in individuals with Alagille syndrome (Heritage et al. 2000. PubMed ID: 11058898; Jurkiewicz et al. 2014. PubMed ID: 24748328; Li et al. 2015. PubMed ID: 26076142; Liu et al. 2018. PubMed ID: 30074189). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.