ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.389_391TCA[1] (p.Ile131del) (rs781818082)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619988 SCV000735421 uncertain significance Cardiovascular phenotype 2016-06-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000645204 SCV000766946 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2017-09-25 criteria provided, single submitter clinical testing This variant, c.392_394delTCA, results in the deletion of 1 amino acid(s) of the JUP protein (p.Ile131del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 402991). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455097 SCV000539413 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with ARVC (PMID 20152563)
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786329 SCV000925104 uncertain significance not provided 2017-11-01 no assertion criteria provided provider interpretation p.Ile131del (c.392_394delTCA) in exon 3 of the JUP gene (NM_002230.2; chr17-39925744-TGA-) SCICD Classification: variant of uncertain significance based on sparse case data and lack of functional data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: JUP: JUP encodes plakoglobin, an integral protein in the desmosome. Disruption in the desmosome results in cardiomyocytes that are partciularly sensitive to mechanical stress. Pathogenic variants in JUP are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and Naxos disease, an autosomal recessive disease with a cardio-cutaneous phenotype. Two other variants in ClinVar with in-frame dels or dups of one amino acid: -One classified as pathogenic: Asimaki et al. (2007) identified a heterozygous 3-bp insertion (118_119GCA) in the plakoglobin gene predicted to insert an extra serine residue at position 39 in the N terminus of the protein (S39_K40insS). -One classified as VUS by Illumina, with no clinical data. Missense and loss of function variants in JUP are more prevalent in cases of cardiomyopathy vs. Controls (OR=7.8 for missense variants; OR=28.1 for loss of function variants). This variant is located in the helix domain of plakoglobin. Amino acid 131 is very close to an armadillo (ARM) domain (position 132-171), which is sufficient for binding other desmosomal proteins like DSG1 and this first ARM domain associated with CTNNA1. Association with DSC1 requires both ends of the ARM domain to be present. Deletion of amino acid isoleucine at position 131 may shift the position of these structural domains; however, this has not been proven with functional studies (http://www.uniprot.org/uniprot/P14923; Choi et al 2009) Case data (not including our patient): 2 · ClinVar: submitted by 1 lab · Laboratory for Molecular Medicine: seen in 1 patient referred for whole genome/exome sequencing. Per Meg Crawley at LMM: this variant was seen on a research basis from an outside hospital and they did not receive any clinical information for the project. They classified it as a VUS and did not report it out. · Xu et al 2011: This variant was seen in 1 out of 198 patients with ARVC referred for genetic testing. Emailed author for clinical details. Segregation data: none reported. emailed author for details Functional data: none reported Conservation data: The isoleucine at codon 131 is completely conserved across species. Neighboring amino acids are also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 121,388 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,061 individuals of European descent (MAF=0.0009%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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