ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.427G>A (p.Ala143Thr) (rs375788626)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471931 SCV000550408 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 143 of the JUP protein (p.Ala143Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs375788626, ExAC 0.04%). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20525856, 25445213). ClinVar contains an entry for this variant (Variation ID: 201811). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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 RCV000183485 SCV000271862 uncertain significance not specified 2017-09-04 criteria provided, single submitter clinical testing The p.Ala143Thr variant in JUP has been reported in 2 individuals with ARVC (LaG erche 2010; Green 2015). It has been also identified in 4/18780 of East Asian ch romosomes and 15/124482 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375788626). Computational pre diction tools and conservation analysis suggest that the p.Ala143Thr variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Ala143Thr varia nt is uncertain.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786327 SCV000925102 uncertain significance not provided 2017-06-26 no assertion criteria provided provider interpretation p.Ala143Thr (c.427G>A) in exon 3 of the JUP gene (NM_002230.2) Given that variants in this gene are not strongly associated with HCM and that this variant has been seen at a relatively high frequency in the general population, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 4 unrelated cases of ARVC (not including this patient's family). The case data is weak. This variant is present in ClinVar and is classified as a variant of uncertain significance. It is also classified as a variant of uncertain significance by the Laboratory for Molecular Medicine. LMM has seen it in 1 individual. This variant was reported in 2 of 27 individuals with ARVC (Green et al 2015). The purpose of this study was to design and validate an NGS test panel for ARVC. It was also present in 1 out of 47 athletes with an ARVC phenotype (La Gerche et al 2010). Per the test report, "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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." The alanine at codon 143 is completely conserved across species. No other variants have been reported in association with disease at this codon. The variant was reported online in 24 of 136,360 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 4 of 9,390 individuals of East Asian descent (MAF=0.02%), 15 of 62,241 individuals of European descent, 2 of 12,393 individuals of Finnish descent, 2 of 17,104 individuals of Latino descent and 1 of 3,189 individuals of other descent. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.