ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1366G>A (p.Val456Ile) (rs78437817)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157250 SCV000206980 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-08-04 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769491 SCV000900886 uncertain significance Cardiomyopathy 2016-05-05 criteria provided, single submitter clinical testing
GeneDx RCV000223572 SCV000235937 likely benign not specified 2016-11-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000333556 SCV000402732 uncertain significance Naxos disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000157250 SCV000402733 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000223572 SCV000917550 likely benign not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: JUP c.1366G>A (p.Val456Ile) results in a conservative amino acid change located in the Armadillo 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 0.00029 in 277054 control chromosomes (gnomAD). The observed variant frequency is approximately 12-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1366G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000474354 SCV000550394 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 456 of the JUP protein (p.Val456Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs78437817, ExAC 0.05%) but has not been reported in the literature in individuals with a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 180375). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000223572 SCV000270294 likely benign not specified 2016-01-07 criteria provided, single submitter clinical testing p.Val456Ile in exon 8 of JUP: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 11 species, including the chimp, marmoset, dolphin and killer whale have an i soleucine (Ile) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of im pact to the protein. It has been identified in 33/66682 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs 78437817).

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