ClinVar Genomic variation as it relates to human health

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)

The c.392_394delTCA variant (also known as p.I131del) is located in coding exon 2 of the JUP gene. This variant results from an in-frame TCA deletion at nucleotide positions 392 to 394. This results in the in-frame deletion of an isoleucine at codon 131. This variant has been reported in an arrhythmogenic right ventricular cardiomyopathy cohort, but clinical details were limited (Xu T et al, J. Am. Coll. Cardiol. 2010 Feb; 55(6):587-97). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.

The c.392_394del variant identified in the JUP gene is predicted to result in deletion of one amino acid [p.(Ile131del)] without causing a shift in the reading frame (in-frame deletion). This variant is observed in 12 individuals across population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. This variant has been identified in one individual affected with arrhythmogenic right ventricular cardiomyopathy [PMID: 20152563], and has also been reported four times in ClinVar as a Variant of Uncertain Significance (ClinVarID:402991). In silico predictions are not available for this variant. Based on the available evidence, the c.392_394del p.(Ile131del) variant identified in the JUP gene is reported as a Variant of Uncertain Significance.

This variant, c.392_394del, 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 present in population databases (rs781818082, gnomAD 0.0009%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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.

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).