ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.1324A>T (p.Ile442Phe)

gnomAD frequency: 0.00002  dbSNP: rs142213474
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171958 SCV000050952 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171958 SCV000235958 uncertain significance not provided 2020-08-06 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics RCV000618640 SCV000736428 likely benign Cardiovascular phenotype 2022-10-06 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.
Invitae RCV001072022 SCV001237364 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 442 of the JUP protein (p.Ile442Phe). This variant is present in population databases (rs142213474, gnomAD 0.01%). This missense change has been observed in individual(s) with primary electrical disease and hypertrophic cardiomyopathy (PMID: 25351510, 28341588). ClinVar contains an entry for this variant (Variation ID: 191671). 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 disruptive. 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.
Illumina Laboratory Services, Illumina RCV001124750 SCV001283737 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.
Illumina Laboratory Services, Illumina RCV001124751 SCV001283738 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824660 SCV002074501 uncertain significance not specified 2022-01-31 criteria provided, single submitter clinical testing Variant summary: JUP c.1324A>T (p.Ile442Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251428 control chromosomes. The observed variant frequency is approximately 8 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.1324A>T has been reported in the literature as a VUS/rare variant in settings of multigene panel testing in an individual with primary electric disease and in an individual with hypertrophic cardiomyopathy (HCM) (example, Proost_2017, Lopez_2013). These report(s) 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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