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

gnomAD frequency: 0.00002  dbSNP: rs142213474

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001072022	SCV001237364	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-11-11	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.