ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.509C>T (p.Ser170Leu) (rs782284038)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588554 SCV000235946 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The S170L variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for arrhythmia genetic testing at GeneDx, although this individual harbored additional cardiogenetic variants and no segregation data are available. This variant is also observed at a global allele frequency of 11/267372 (0.004%) alleles in large population cohorts, including 7/124788 (0.006%) alleles from individuals of European (non-Finnish) ancestry (Lek et al., 2016). The S170L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Illumina Clinical Services Laboratory,Illumina RCV000321164 SCV000402752 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.
Illumina Clinical Services Laboratory,Illumina RCV000378103 SCV000402753 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.
Invitae RCV000541609 SCV000645742 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 170 of the JUP protein (p.Ser170Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs794729034, ExAC 0.006%). This variant has not been reported in the literature in individuals with JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 201812). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV001175368 SCV000699466 likely benign not specified 2019-09-16 criteria provided, single submitter clinical testing Variant summary: JUP c.509C>T (p.Ser170Leu) results in a non-conservative amino acid change located in the Armadillo domain of 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 4.6e-05 in 241372 control chromosomes. The observed variant frequency is approximately 4.5 fold the estimated maximal allele frequency expected for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.509C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating an impact on protein function have been reported. Three other 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. Based on the evidence outlined above, the variant was classified as likely benign.

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