ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr19Ile variant in JUP has been reported in 1 adult with DCM as well as 3 relatives who had arrhythmia (2) or low ejection fraction (1)(Garcia-Pavia 2011) and 1 individ ual with ARVC (den Haan 2009). This variant has been identified in 11/63034 Euro pean and 2/10852 Latino chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr19Ile variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, wh ile there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.

The JUP c.56C>T (p.Thr19Ile) variant has been reported in two studies and is found in a heterozygous state in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one individual with dilated cardiomyopathy (DCM) (den Haan et al. 2009; Garcia-Pavia et al. 2011). The father of the proband with DCM was presumed to carry the variant, but had died of sudden cardiac death at age 53 and was not tested (Garcia-Pavia et al. 2011). The variant was also found in four unaffected relatives of the proband with DCM, with three showing other cardiovascular abnormalities including coronary artery disease, palpitations, and atrial fibrillation (Garcia-Pavia et al. 2011). The p.Thr19Ile variant was absent from 800 control chromosomes (den Haan et al. 2009; Garcia-Pavia et al. 2011), but is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Thr19Ile variant is classified as a variant of unknown significance, but suspicious for pathogenicity for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Reported in association with dilated cardiomyopathy (DCM) (Garcia-Pavia et al., 2001; Sanchez et al., 2016), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (den Haan et al., 2009; Tan et al., 2010; Bhonsale et al., 2013; Sabater-Molina et al., 2013; te Riele et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27930701, 21859740, 20031617, 20857253, 23671136, 26187847, 27037756, 28471438, 31402444, 34026867, 35581137)

The JUP c.56C>T; p.Thr19Ile variant (rs570878629) is reported in the literature in several individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (Bhonsale 2015, den Haan 2009, Garcia-Pavia 2011, Haggerty 2017, Sanchez 2016, Tan 2010). This variant is also reported in ClinVar (Variation ID: 179756), and is found in the general population with an overall allele frequency of 0.012% (33/280798 alleles) in the Genome Aggregation Database. The threonine at codon 19 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.204). However, given the lack of functional data, the significance of this variant is uncertain at this time. References: Bhonsale A et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J. 2015 Apr 7;36(14):847-55. PMID: 25616645. den Haan AD et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. PMID: 20031617. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Haggerty CM et al. Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. Genet Med. 2017 Nov;19(11):1245-1252. PMID: 28471438. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701. Tan BY et al. Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Transl Res. 2010 Dec;3(6):663-73. PMID: 20857253.

This sequence change results in a missense variant in the JUP gene ( p.cThr19Ile)). This variant is present in population databases with a prevalence of 33/280798in GnomAD (BS1). This variant has been reported in the literature. It was found in different individuals with ARVC and co-seggregated with disease in a family with DCM and arrhythmia (Garcia-Pavia 2011; den Haan 2009; PP1). The variant has been identified in a case of SCD with DCM and additional cardiac variants (Haggerty CM et al, 2017; BP5). No functional data are available. Prediction programs show conflicting results ( Align GVGD C0; Polyphen-2-HumDiv possibly damaging; Polyphen-2-HumVar possivley damaging; SIFT: tolerated; MutationTaster: disease causing). In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (criteria for benign and pathogenic are contradictory: BS1, PP1; BP5).

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 19 of the JUP protein (p.Thr19Ile). This variant is present in population databases (rs570878629, gnomAD 0.03%). This missense change has been observed in individual(s) with JUP-related conditions (PMID: 20031617, 21859740, 25616645, 27930701). ClinVar contains an entry for this variant (Variation ID: 179756). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.