Submissions for variant NM_002230.4(JUP):c.708-4C>G

gnomAD frequency: 0.00014  dbSNP: rs201313464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039086	SCV000062764	likely benign	not specified	2016-05-18	criteria provided, single submitter	clinical testing	c.708-4C>G in intron 4 of JUP: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It has been identified in 4/10616 Latino chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs201313464).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474347	SCV000560959	likely benign	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619953	SCV000735670	benign	Cardiovascular phenotype	2022-05-27	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001610335	SCV001840484	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798127	SCV002043160	likely benign	Cardiomyopathy	2020-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039086	SCV004804340	benign	not specified	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: JUP c.708-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 244770 control chromosomes. The observed variant frequency is approximately 25.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. c.708-4C>G has been reported in the literature in individuals affected with dilated cardiomyopathy without evidence of causality (Pugh_2014). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45855). Based on the evidence outlined above, the variant was classified as benign.