ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.2207C>T (p.Pro736Leu) (rs151178348)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757414 SCV000885623 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing The p.Pro736Leu variant (rs151178348) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the European Non-Finnish population (identified on 58 out of 125,094 chromosomes) and has been reported to the ClinVar database (Variation ID: 45847). The proline at position 736 is weakly conserved and computational analyses of the effects of the p.Pro736Leu variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro736Leu variant with certainty.
Ambry Genetics RCV000621167 SCV000734941 uncertain significance Cardiovascular phenotype 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157253 SCV000206983 uncertain significance Left ventricular noncompaction cardiomyopathy 2014-07-23 no assertion criteria provided clinical testing
GeneDx RCV000757414 SCV000235939 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the JUP gene. The P736L variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been reported in other individuals who underwent genetic testing for cardiomyopathy at GeneDx. The P736L variant is observed in 0.046% (58/125094) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the P736L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Invitae RCV000463617 SCV000550410 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 736 of the JUP protein (p.Pro736Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs151178348, ExAC 0.04%). This variant has been reported in one individual affected with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 45847). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039078 SCV000062756 uncertain significance not specified 2015-04-01 criteria provided, single submitter clinical testing The p.Pro736Leu variant in JUP has been identified by our laboratory in 4 indivi duals (1 child with HCM, 1 adult and 1 child with DCM, and 1 child with RCM), 2 of whom carried clinically significant variants in other genes. This variant has also been identified in 0.04% (28/64990) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs151178348). Proline (Pro) at position 736 is not conserved in evolution and 1 mammal (Tenre c) carries a leucine (Leu) at this position, raising the possibility that this c hange may be tolerated. In summary, the clinical significance of the p.Pro736Leu variant is uncertain.

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