ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1876G>A (p.Ala626Thr) (rs782547688)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183505 SCV000235965 uncertain significance not provided 2019-01-22 criteria provided, single submitter clinical testing The A626T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A626T 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. The A626T 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. Additionally, this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000472032 SCV000550391 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2016-11-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 626 of the JUP protein (p.Ala626Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs782547688, ExAC 0.009%) but has not been reported in the literature in individuals with a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 201828). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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