ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1996G>A (p.Val666Met)

gnomAD frequency: 0.00003  dbSNP: rs372369061
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781482 SCV000919546 uncertain significance not specified 2018-10-30 criteria provided, single submitter clinical testing Variant summary: JUP c.1996G>A (p.Val666Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277246 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1996G>A, has been reported in the literature in an individual affected with sudden unexplained death (Lin_2017). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001369585 SCV001566027 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 666 of the JUP protein (p.Val666Met). This variant is present in population databases (rs372369061, gnomAD 0.003%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119, 35087879). ClinVar contains an entry for this variant (Variation ID: 633278). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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