Submissions for variant NM_002230.4(JUP):c.545C>T (p.Ser182Leu)

gnomAD frequency: 0.00013  dbSNP: rs145592971

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039084	SCV000062762	uncertain significance	not specified	2012-05-22	criteria provided, single submitter	clinical testing	The Ser182Leu variant in JUP has been identified in 1/7018 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/; dbSNP rs145592971). Computational analyses (biochemic al amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the As p149Asn variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Additional information is needed to fully a ssess the clinical significance of the Ser182Leu variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039084	SCV000699467	likely benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: JUP c.545C>T (p.Ser182Leu) results in a non-conservative amino acid change located in one of the armadillo repeats (IPR000225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 386114 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.00026 in the gnomAD database (gnomAD v2.1 exomes dataset, and gnomAD v3 genomes dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.545C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Another clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058398	SCV001222964	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 182 of the JUP protein (p.Ser182Leu). This variant is present in population databases (rs145592971, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 45853). 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.
Ambry Genetics	RCV002345304	SCV002649727	likely benign	Cardiovascular phenotype	2022-04-27	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.
GeneDx	RCV003234936	SCV003933639	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with a JUP-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 31983221)