Submissions for variant NM_002230.4(JUP):c.1729C>T (p.Arg577Cys)

gnomAD frequency: 0.00003  dbSNP: rs782354654

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545274	SCV000645728	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 577 of the JUP protein (p.Arg577Cys). This variant is present in population databases (rs782354654, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 31275992). ClinVar contains an entry for this variant (Variation ID: 468747). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on JUP function (PMID: 31275992). 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	RCV000618150	SCV000736791	uncertain significance	Cardiovascular phenotype	2024-12-04	criteria provided, single submitter	clinical testing	The p.R577C variant (also known as c.1729C>T), located in coding exon 9 of the JUP gene, results from a C to T substitution at nucleotide position 1729. The arginine at codon 577 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported as occurring de novo in an individual with some features consistent with arrhythmogenic right ventricular cardiomyopathy. In vitro studies by the same group suggest this variant may impact expression of other proteins (Liu L et al. Biomed Res Int. 2019 May;2019:9103860). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532951	SCV001748767	uncertain significance	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: JUP c.1729C>T (p.Arg577Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1729C>T has been reported in the literature as a de novo variant in a patient affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Liu_2019). This same report shows experimental evidence of decreased experssion of DSG2 and Connexin 43 in mutated cells via Western blot analysis. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000545274	SCV002781604	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-10-11	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000545274	SCV003920084	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-03-30	criteria provided, single submitter	clinical testing	JUP NM_002230.2 exon 10 p.Arg577Cys (c.1729C>T): This variant has not been reported in the literature and is present in 0.01% (2/18388) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/17-39914695-G-A). This variant is present in ClinVar (Variation ID:468747). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Molecular Genetics, Royal Melbourne Hospital	RCV005250075	SCV005900470	uncertain significance	Arrhythmogenic right ventricular dysplasia 12	2024-08-05	criteria provided, single submitter	clinical testing