Submissions for variant NM_002230.4(JUP):c.578T>C (p.Met193Thr)

gnomAD frequency: 0.00009  dbSNP: rs139496777

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208130	SCV000263963	uncertain significance	Primary dilated cardiomyopathy	2015-09-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468133	SCV000550405	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 193 of the JUP protein (p.Met193Thr). This variant is present in population databases (rs139496777, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 222661). 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.
GeneDx	RCV001536180	SCV001752902	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing	Identified in an individual with DCM in the published literature (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222661; 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: 31983221, 27532257)
Ambry Genetics	RCV002354587	SCV002648944	likely benign	Cardiovascular phenotype	2022-03-07	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	RCV000468133	SCV002782350	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-09-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701274	SCV005205109	likely benign	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: JUP c.578T>C (p.Met193Thr) results in a non-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 7.2e-05 in 248456 control chromosomes. The observed variant frequency is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06). c.578T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Mazzarotto_2020, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31983221, 27532257). ClinVar contains an entry for this variant (Variation ID: 222661). Based on the evidence outlined above, the variant was classified as likely benign.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656166	SCV000678360	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome