Total submissions: 7
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. |
Gene |
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, |
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, |
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, |
RCV000996541 | SCV001931923 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000996541 | SCV001969429 | uncertain significance | not provided | no assertion criteria provided | clinical testing |