ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1372G>A (p.Ala458Thr) (rs139559495)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489721 SCV000577061 uncertain significance not provided 2018-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The A458T variant has been published in one patient with HCM (Lopes et al., 2013); however, additional clinical details were not provided. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A458T 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. This substitution occurs at a position that is conserved across most species with threonine being the wild type in at least one species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000546052 SCV000645725 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 458 of the JUP protein (p.Ala458Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs139559495, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 426584). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Ambry Genetics RCV000621825 SCV000735783 uncertain significance Cardiovascular phenotype 2017-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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