Submissions for variant NM_002230.4(JUP):c.529C>T (p.Arg177Trp)

gnomAD frequency: 0.00007  dbSNP: rs148484473

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183487	SCV000235947	uncertain significance	not provided	2023-10-30	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy; however, specific clinical information was not provided (PMID: 31983221, 27532257); 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: 31983221, 27532257, 31402444)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050476	SCV001214585	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 177 of the JUP protein (p.Arg177Trp). This variant is present in population databases (rs148484473, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of JUP-related conditions (PMID: 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 201813). 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. 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	RCV002345642	SCV002645690	likely benign	Cardiovascular phenotype	2022-06-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV001050476	SCV002787058	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-08-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955111	SCV004774845	uncertain significance	JUP-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The JUP c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Trp. This variant has been reported in one individual with arrhythmogenic right ventricular cardiomyopathy (Table S1A, Walsh et al. 2017. PubMed ID: 27532257) and another individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant was also reported in a patient with hypertrophic cardiomyopathy and a family history of Wolff-Parkinson-White syndrome who was found to harbor a pathogenic variant in the PRKAG2 gene (Linares et al. 2023. DOI: 10.23937/2643-3966/1710057). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.