ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.2178C>T (p.Ile726=) (rs141295561)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039077 SCV000062755 likely benign not specified 2012-06-19 criteria provided, single submitter clinical testing Ile726Ile in exon 14 of JUP: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence. It has been identified in 0.1% (6/7020) of Europea n American chromosomes from a broad population by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS; dbSNP rs141295561). Ile726Ile in exon 1 4 of JUP (rs141295561; allele frequency= 0.1%, 6/7020) **
GeneDx RCV000039077 SCV000169894 benign not specified 2013-12-09 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.
Invitae RCV000547915 SCV000645734 likely benign Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618792 SCV000736806 likely benign Cardiovascular phenotype 2017-04-04 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000039077 SCV001158337 likely benign not specified 2019-04-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001124560 SCV001283533 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 Clinical Services Laboratory,Illumina RCV001124561 SCV001283534 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 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.
Integrated Genetics/Laboratory Corporation of America RCV000039077 SCV001362159 benign not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: JUP c.2178C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational 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 0.00019 in 249902 control chromosomes. The observed variant frequency is approximately 18.81 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.2178C>T has been reported in the literature (Pugh_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.

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