ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.568G>A (p.Val190Met) (rs370143312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183488 SCV000235948 uncertain significance not provided 2014-07-10 criteria provided, single submitter clinical testing p.Val190Met (GTG>ATG): c.568 G>A in exon 4 of the JUP gene (NM_002230.2). The V190M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V190M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V190M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000688743 SCV000816366 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 190 of the JUP protein (p.Val190Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs370143312, 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: 201814). 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: "Probably 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.
Integrated Genetics/Laboratory Corporation of America RCV001193379 SCV001362157 likely benign not specified 2019-12-16 criteria provided, single submitter clinical testing Variant summary: JUP c.568G>A (p.Val190Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 247284 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.568G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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