ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.2069A>G (p.Asn690Ser) (rs147628503)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208373 SCV000263967 uncertain significance Paroxysmal familial ventricular fibrillation 1 2015-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000150847 SCV000235967 uncertain significance not specified 2017-02-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The N690S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been seen in multiple individuals who had DNA-based testing for ARVC at GeneDx, and is also reported in ClinVar as a variant of uncertain significance in association with cardiac arrhythmia by the Laboratory for Molecular Medicine (Landrum et al., 2014). The N690S variant was not observed with any significant frequency 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. This substitution occurs at a position that is conserved mammals. However, N690S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Only one other definitive missense variant in a nearby residue (Y693C) has been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000227308 SCV000287311 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 690 of the JUP protein (p.Asn690Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs147628503, 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 a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 163710). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, this variant has uncertain impact on JUP function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150847 SCV000198397 uncertain significance not specified 2015-02-10 criteria provided, single submitter clinical testing The p.Asn690Ser variant in JUP has been identified by our laboratory in 1 adult with HCM who carried a pathogenic variant in another gene that was sufficient to explain the disease. It has also been identified in 8/65254 of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs147628503). Computational prediction tools and conservation analysis sug gest that the p.Asn690Ser variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, the clinic al significance of the p.Asn690Ser variant is uncertain.

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