Submissions for variant NM_002230.4(JUP):c.892G>A (p.Gly298Ser)

gnomAD frequency: 0.00009  dbSNP: rs199597864

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587522	SCV000235953	uncertain significance	not provided	2023-03-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000251525	SCV000319824	likely benign	Cardiovascular phenotype	2023-07-26	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.
Invitae	RCV000475317	SCV000550409	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the JUP protein (p.Gly298Ser). This variant is present in population databases (rs199597864, gnomAD 0.07%). 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: 201819). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293416	SCV000699471	uncertain significance	not specified	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: JUP c.892G>A (p.Gly298Ser) 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 0.00016 in 251328 control chromosomes (gnomAD). The observed variant frequency is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.892G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587522	SCV001978678	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587522	SCV001979735	uncertain significance	not provided		no assertion criteria provided	clinical testing