ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1035G>C (p.Lys345Asn) (rs150194093)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000143904 SCV000188775 likely benign Primary familial hypertrophic cardiomyopathy 2013-12-30 no assertion criteria provided clinical testing
GeneDx RCV000767065 SCV000235955 uncertain significance not provided 2014-06-23 criteria provided, single submitter clinical testing p.Lys345Asn (AAG>AAC): c.1035 G>C in exon 6 of the JUP gene (NM_002230.2). The K345N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K345N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K345N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in ARVC panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000278374 SCV000402740 uncertain significance Naxos disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000335744 SCV000402741 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000705144 SCV000834129 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 345 of the JUP protein (p.Lys345Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs150194093, 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 disease. ClinVar contains an entry for this variant (Variation ID: 155802). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183495 SCV000271859 uncertain significance not specified 2015-03-05 criteria provided, single submitter clinical testing The p.Lys345Asn variant in JUP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 9/67674 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 50194093). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Lys345Asn variant is uncertain.

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