ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.607C>T (p.Arg203Cys) (rs147354282)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780357 SCV000917549 uncertain significance not specified 2018-06-11 criteria provided, single submitter clinical testing Variant summary: JUP c.607C>T (p.Arg203Cys) results in a non-conservative amino acid change located in one of the Armadillo repeats (IPR000225) 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 6.2e-05 in 273732 control chromosomes (in gnomAD). The observed variant frequency is approximately 6.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), suggesting that the variant is benign. To our knowledge, no occurrence of c.607C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000234226 SCV000287316 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2017-02-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 203 of the JUP protein (p.Arg203Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs147354282, ExAC 0.008%) but has not been reported in the literature in individuals with a JUP-related disease. ClinVar contains an entry for this variant (Variation ID: 239107). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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