Submissions for variant NM_002230.4(JUP):c.1213G>A (p.Val405Ile) (rs200019016)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473876	SCV000550400	uncertain significance	Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12	2016-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 405 of the JUP protein (p.Val405Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs200019016, ExAC 0.08%) but has not been reported in the literature in individuals with a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 163718). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000150849	SCV000198403	uncertain significance	not specified	2013-10-15	criteria provided, single submitter	clinical testing	The Val405Ile variant in JUP has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 1/192 Kenyan chromosomes by the 100 0 Genomes Project (dbSNP rs200019016). Lack of evolutionary conservation suggest s that the variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. Additional information is needed to f ully assess the clinical significance of the Val405Ile variant.

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