ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.475G>T (p.Val159Leu)

gnomAD frequency: 0.00008  dbSNP: rs782702266
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542692 SCV000645739 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2022-10-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 159 of the JUP protein (p.Val159Leu). This variant is present in population databases (rs782702266, gnomAD 0.007%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome (PMID: 18672408, 25820315, 26230511). ClinVar contains an entry for this variant (Variation ID: 468754). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
GeneDx RCV000996541 SCV001792732 uncertain significance not provided 2020-12-10 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 468754; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 32268277, 25820315, 18672408, 26230511, 20152563)
Ambry Genetics RCV002330914 SCV002633650 likely benign Cardiovascular phenotype 2023-03-23 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV000542692 SCV002782504 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2021-08-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479157 SCV004222704 likely benign not specified 2023-11-15 criteria provided, single submitter clinical testing Variant summary: JUP c.475G>T (p.Val159Leu) 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 5.2e-05 in 1552702 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. c.475G>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and Brugada Syndrome (examples: Xu_2010, Allegue_2015, Iglesias_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (PKP2 c.2146-1G>C), providing supporting evidence for a benign role (Xu_2010). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000996541 SCV001931923 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000996541 SCV001969429 uncertain significance not provided no assertion criteria provided clinical testing

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