ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1355C>T (p.Thr452Met) (rs781888888)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183500 SCV000235960 uncertain significance not provided 2014-06-24 criteria provided, single submitter clinical testing p.Thr452Met (ACG>ATG): c.1355 C>T in exon 8 of the JUP gene (NM_002230.2). The T452M variant has not been published as a mutation or as a benign polymorphism to our knowledge. The T452M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the T452M 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. Moreover, this substitution occurs at a position that is conserved in mammals. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000819254 SCV000959904 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 452 of the JUP protein (p.Thr452Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs781888888, ExAC 0.01%), 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: 201824). 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: "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.

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