Submissions for variant NM_002230.4(JUP):c.2105G>A (p.Arg702His)

gnomAD frequency: 0.00004  dbSNP: rs200690479

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171956	SCV000050948	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155621	SCV000205329	uncertain significance	not specified	2015-05-16	criteria provided, single submitter	clinical testing	The p.Arg702His variant in JUP has been identified by our laboratory in 1 Caucas ian individual with CPVT. However, this individual carried a pathogenic variant in RYR2, and the p.Arg702His variant was also found in an apparently unaffected member of the same family. This variant has also been identified in 8/66036 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs200690479). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg702His variant is uncertain.
Invitae	RCV000559192	SCV000645732	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the JUP protein (p.Arg702His). This variant is present in population databases (rs200690479, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 178849). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Ambry Genetics	RCV000619443	SCV000737685	uncertain significance	Cardiovascular phenotype	2016-08-16	criteria provided, single submitter	clinical testing	The p.R702H variant (also known as c.2105G>A), located in coding exon 13 of the JUP gene, results from a G to A substitution at nucleotide position 2105. The arginine at codon 702 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This variant was previously reported in the SNPDatabase as rs200690479. Based on data from ExAC, the A allele has an overall frequency of <0.01% (6/104582). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622902	SCV000740581	uncertain significance	Left ventricular noncompaction	2017-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000171956	SCV001758212	uncertain significance	not provided	2019-10-31	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 178849; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798512	SCV002043155	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000559192	SCV002792730	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-10-20	criteria provided, single submitter	clinical testing