Submissions for variant NM_002230.4(JUP):c.1280C>T (p.Thr427Met)

gnomAD frequency: 0.00004  dbSNP: rs781982717

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466222	SCV000550396	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-12-24	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 427 of the JUP protein (p.Thr427Met). This variant is present in population databases (rs781982717, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (PMID: 20864495, 24125834). ClinVar contains an entry for this variant (Variation ID: 409984). 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 tolerated. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001753895	SCV001472742	uncertain significance	not provided	2020-07-24	criteria provided, single submitter	clinical testing	The JUP c.1280C>T; p.Thr427Met variant (rs781982717) is reported in the literature in several individuals with a diagnosis or suspicion of arrhythmogenic right ventricular cardiomyopathy (Bao 2013, Christensen 2010). This variant is found in the Latino population with an overall allele frequency of 0.02% (6/35540 alleles) in the Genome Aggregation Database. The threonine at codon 427 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Thr427Met variant is uncertain at this time. References: Bao J et al. Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet. 2013;6(6):552-556. Christensen et al. Wide Spectrum of Desmosomal Mutations in Danish Patients With Arrhythmogenic Right Ventricular Cardiomyopathy. J Med Genet. 2010 Nov;47(11):736-44.
GeneDx	RCV001753895	SCV001985386	uncertain significance	not provided	2019-05-20	criteria provided, single submitter	clinical testing	Reported in association with ARVC; however, no additional clinical information was provided (Christensen et al., 2010; Bao et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24125834, 20864495, 31402444)
Ambry Genetics	RCV002374789	SCV002692547	likely benign	Cardiovascular phenotype	2022-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.