ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.436G>A (p.Glu146Lys)

gnomAD frequency: 0.00002  dbSNP: rs146581757
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819263 SCV000959913 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 146 of the JUP protein (p.Glu146Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs146581757, ExAC 0.01%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 28855170). 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.
GeneDx RCV001759599 SCV001985158 uncertain significance not provided 2020-03-20 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 661772; 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: 29606362, 28855170, 32600061)
Ambry Genetics RCV002332696 SCV002632972 uncertain significance Cardiovascular phenotype 2022-10-12 criteria provided, single submitter clinical testing The p.E146K variant (also known as c.436G>A), located in coding exon 2 of the JUP gene, results from a G to A substitution at nucleotide position 436. The glutamic acid at codon 146 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a left ventricular non-compaction (LVNC) cohort and an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Wang C et al. J Am Heart Assoc, 2017 Aug;6:[ePub ahead of print]; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000819263 SCV002784969 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2021-11-12 criteria provided, single submitter clinical testing

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