Submissions for variant NM_002230.4(JUP):c.1219G>A (p.Val407Ile)

gnomAD frequency: 0.00004  dbSNP: rs370913228

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645194	SCV000766936	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 407 of the JUP protein (p.Val407Ile). This variant is present in population databases (rs370913228, gnomAD 0.007%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495). ClinVar contains an entry for this variant (Variation ID: 536625). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420778	SCV001623131	uncertain significance	not specified	2021-05-03	criteria provided, single submitter	clinical testing	Variant summary: JUP c.1219G>A (p.Val407Ile) results in a conservative amino acid change located in the Armadillo repeat domain (IPR000225) of 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 2e-05 in 251350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1219G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia (ARVD), sudden unexplained death, dilated cardiomyopathy and in individuals who underwent exome sequencing (Christensen_2010, Santori_2015, Haggerty_2017, Verdonschot_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002360594	SCV002659488	uncertain significance	Cardiovascular phenotype	2023-04-14	criteria provided, single submitter	clinical testing	The p.V407I variant (also known as c.1219G>A), located in coding exon 7 of the JUP gene, results from a G to A substitution at nucleotide position 1219. The valine at codon 407 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in an arrhythmogenic right ventricular cardiomyopathy (ARVC) case (Christensen AH et al, 2010 Nov;47:736-44). This variant has also been seen in exome, sudden unexplained death, and dilated cardiomyopathy cohorts, but clinical details were limited (Andreasen C et al, 2013 Sep;21:918-28; Santori M et al, 2015 Oct;100:952-6; Haggerty CM et al, 2017 11;19:1245-1252; Verdonschot JAJ et al. Circ Genom Precis Med. 2020 Oct;13(5):476-487). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000645194	SCV003920085	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-03-30	criteria provided, single submitter	clinical testing	JUP NM_002230.2 exon 8 p.Val407Ile (c.1219G>A): This variant has been reported in the literature in one individual with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (Christensen 2010 PMID:20864495). This variant is present in 1/15304 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370913228) and is present in ClinVar (Variation ID:536625). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000996536	SCV001743710	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000996536	SCV001952906	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000996536	SCV001972805	uncertain significance	not provided		no assertion criteria provided	clinical testing