ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.352G>A (p.Glu118Lys) (rs149004293)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171964 SCV000050951 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678710 SCV000804875 uncertain significance Left ventricular hypertrophy 2016-01-22 no assertion criteria provided clinical testing
GeneDx RCV000171964 SCV000536629 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. While the E118K variant has not been published as pathogenic or been reported as benign to our knowledge, it has been reported as a variant of uncertain significance in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). 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 E118K 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 species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000705755 SCV000834768 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 118 of the JUP protein (p.Glu118Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs149004293, ExAC 0.04%). This variant has not been reported in the literature in individuals with JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 191676). 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, 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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