ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.892G>A (p.Gly298Ser) (rs199597864)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587522 SCV000235953 uncertain significance not provided 2014-04-03 criteria provided, single submitter clinical testing p.Gly298Ser (GGC>AGC): c.892 G>A in exon 5 of the JUP gene (NM_002230.2). p.Gly298Ser (GGC>AGC): c.892 G>A in exon 5 of the JUP gene (NM_002230.2). The G298S variant in the JUP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. G298S results in a non-conservative amino acid substitution of a nonpolar Glycine with a polar Serine at a position that is highly conserved across species. In silico analysis predicts G298S is probably damaging to the protein structure/function. The 1000 Genomes database reported the G298S variant in 1/757 European alleles (0.1%). The variant is found in ARVC,CARDIOMYOPATHY,ARRHYTHMIA panel(s).
Ambry Genetics RCV000251525 SCV000319824 uncertain significance Cardiovascular phenotype 2018-09-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000475317 SCV000550409 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 298 of the JUP protein (p.Gly298Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs199597864, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 201819). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Integrated Genetics/Laboratory Corporation of America RCV000587522 SCV000699471 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The JUP c.892G>A (p.Gly298Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured). This variant was found in 9/121140 control chromosomes at a frequency of 0.0000743, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic JUP variant (0.00001), suggesting this variant is likely a benign polymorphism, however the possibility of subclinical cardiac disease in the controls cohorts cannot be entirely ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.

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