ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.926A>G (p.Asn309Ser) (rs140606359)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171961 SCV000054836 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Invitae RCV000467285 SCV000550399 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 309 of the JUP protein (p.Asn309Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs140606359, ExAC 0.01%). This variant has not been reported in the literature in individuals with JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 178042). 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. 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 RCV000154727 SCV000204407 uncertain significance not specified 2013-05-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Asn309Ser varia nt in JUP has not been reported in individuals with cardiomyopathy, but has been identified in 1/8600 European American chromosomes and 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs140606359). Asparagine (Asn) at position 309 is not completely con served in evolutionarily distant species with several (medaka, zebrafish, lampre y, and fruitfly) carrying a serine (Ser; this variant) at this position, suggest ing that this change may be tolerated. Additional computational analyses (bioche mical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that t his variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, the presence of this variant in other species suggests that it is more likely benign, but additional information is needed to fully assess its clinical significance.

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