ClinVar Miner

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

gnomAD frequency: 0.00036  dbSNP: rs78437817
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001719985 SCV000235937 likely benign not provided 2019-04-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; dbSNP rs 78437817).
Illumina Laboratory Services, Illumina RCV000333556 SCV000402732 uncertain significance Naxos disease 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001094480 SCV000402733 uncertain significance Arrhythmogenic right ventricular dysplasia 12 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000474354 SCV000550394 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2024-01-31 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 456 of the JUP protein (p.Val456Ile). This variant is present in population databases (rs78437817, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769491 SCV000900886 likely benign Cardiomyopathy 2021-06-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000223572 SCV000917550 likely benign not specified 2022-12-08 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 region 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 0.00027 in 251292 control chromosomes. The observed variant frequency is approximately 10.98 fold of 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. c.1366G>A has been reported in the literature in one individual affected with peripartum cardiomyopathy who also carried two truncating mutations in other cardiomyopathy-causing genes (TTN, DSP; Csanyi_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: three submitters classified as likely benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV002381507 SCV002697620 likely benign Cardiovascular phenotype 2019-01-02 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Blueprint Genetics RCV000157250 SCV000206980 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-08-04 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.