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 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000378103 SCV000402753 uncertain significance Naxos disease 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588554 SCV000699466 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The JUP c.509C>T (p.Ser170Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 4/118450 control chromosomes at a frequency of 0.0000338, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic JUP variant (0.00001). It is unknown if the carriers have any cardio syndromes. In addition, one clinical diagnostic laboratory classified this variant as variant of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS until more evidence becomes available.
Invitae RCV000541609 SCV000645742 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-11-02 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.

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