ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1667T>C (p.Met556Thr) (rs781884735)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617763 SCV000738222 uncertain significance Cardiovascular phenotype 2017-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000439893 SCV000520046 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing The M556T variant of uncertain significance in the JUP gene has not been published as pathogenic or been reported as benign to our knowledge. M556T 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 M556T 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. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV000231900 SCV000287307 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2016-01-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 556 of the JUP protein (p.Met556Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs781884735, ExAC <0.01%) but has not been reported in the literature in individuals with a JUP-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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