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
Ambry Genetics RCV000251525 SCV000319824 uncertain significance Cardiovascular phenotype 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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).
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.
Invitae RCV000475317 SCV000550409 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2016-04-22 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%) but has not been reported in the literature in individuals with a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 201819). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). However, algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, but has an uncertain impact on splicing. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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