ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.746C>T (p.Thr249Met)

gnomAD frequency: 0.00004  dbSNP: rs377612199
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171962 SCV000050953 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Invitae RCV000699752 SCV000828477 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 249 of the JUP protein (p.Thr249Met). This variant is present in population databases (rs377612199, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 191674). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
AiLife Diagnostics, AiLife Diagnostics RCV000171962 SCV002503208 uncertain significance not provided 2021-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390411 SCV002671341 uncertain significance Cardiovascular phenotype 2023-12-12 criteria provided, single submitter clinical testing The p.T249M variant (also known as c.746C>T), located in coding exon 4 of the JUP gene, results from a C to T substitution at nucleotide position 746. The threonine at codon 249 is replaced by methionine, an amino acid with similar properties. This variant has been reported in a family with catecholaminergic polymorphic ventricular tachycardia (CPVT) that also carried variants in other cardiac-related genes (Gray B et al. Heart Rhythm, 2016 Aug;13:1652-60). This alteration has also been reported in a dilated cardiomyopathy (DCM) cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This alteration has also been reported as a secondary cardiac variant in an exome cohort and in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000699752 SCV002794405 uncertain significance Naxos disease; Arrhythmogenic right ventricular dysplasia 12 2021-09-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003917590 SCV004735423 uncertain significance JUP-related disorder 2023-12-26 criteria provided, single submitter clinical testing The JUP c.746C>T variant is predicted to result in the amino acid substitution p.Thr249Met. This variant has been observed, along with two other variants in TTN and DSG2 genes, in an individual from a cohort of patients with dilated cardiomyopathy (Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000171962 SCV001741095 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000171962 SCV001920878 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000171962 SCV001958889 uncertain significance not provided no assertion criteria provided clinical testing

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