ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.274G>T (p.Gly92Cys) (rs781875765)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000524047 SCV000617047 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The G92C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G92C variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The G92C 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. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000617807 SCV000736419 uncertain significance Cardiovascular phenotype 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000645198 SCV000766940 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2017-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 92 of the JUP protein (p.Gly92Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs781875765, ExAC 0.002%). This variant has not been reported in the literature in individuals with 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: "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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