ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.56C>T (p.Thr19Ile) (rs570878629)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253975 SCV000318937 uncertain significance Cardiovascular phenotype 2013-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000656851 SCV000565085 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The T19I variant has been previously reported in association with DCM (Garcia-Pavia et al., 2001; Sanchez et al., 2016), and ARVC (den Haan et al., 2009; Tan et al., 2010; Bhonsale et al., 2013; Sabater-Molina et al., 2013; te Riele et al., 2015). Garcia-Pavia et al. (2011) reported this variant in a 50 year-old Caucasian male with DCM, atrial fibrillation and non-sustained ventricular tachycardia, and it was found to segregate in one brother with a reduced left ventricular ejection fraction and atrial fibrillation, one brother with atrial fibrillation, one son with palpitations, and one unaffected son. The T19I variant was absent from this individual's mother indicating that the father, who had a history of DCM and sudden cardiac death, was likely an obligate carrier (Garcia-Pavia et al., 2011). However, no informative segregation data are available for the remaining published cases to further clarify the role of this variant in disease. Additionally, the T19I variant was observed in four individuals without ARVC from a cohort of over 30,000 individuals who underwent exome sequencing (Haggerty et al., 2017), and it has been observed in 11/34634 (0.032%) alleles from individuals of Latino ancestry, and in 20/125584 (0.015%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the T19I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000393399 SCV000402762 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 12 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000315534 SCV000402763 uncertain significance Naxos disease 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000692565 SCV000820393 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 19 of the JUP protein (p.Thr19Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs570878629, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and in individuals with dilated cardiomyopathy (DCM) (PMID: 20031617, 21859740, 25616645, 27930701). ClinVar contains an entry for this variant (Variation ID: 179756). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000156554 SCV000206273 uncertain significance not specified 2016-01-20 criteria provided, single submitter clinical testing 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.

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