Submissions for variant NM_002230.4(JUP):c.412G>A (p.Glu138Lys)

gnomAD frequency: 0.00005  dbSNP: rs150245906

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780359	SCV000917552	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: JUP c.412G>A (p.Glu138Lys) results in a conservative amino acid change located in the Armadillo domain of 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 3.3e-05 in 272734 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.412G>A has been reported in the literature, without strong evidence for causality (Walsh_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001049504	SCV001213554	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2022-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 138 of the JUP protein (p.Glu138Lys). This variant is present in population databases (rs150245906, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of JUP-related conditions (PMID: 27532257, 30847666). ClinVar contains an entry for this variant (Variation ID: 632865). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256955	SCV001433488	uncertain significance	Conduction disorder of the heart	2019-07-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001592960	SCV001814275	uncertain significance	not provided	2019-07-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31402444, 30847666, 27532257)
Ambry Genetics	RCV002332568	SCV002628547	likely benign	Cardiovascular phenotype	2022-03-24	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, Fulgent Genetics	RCV001049504	SCV002793684	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-07-28	criteria provided, single submitter	clinical testing