Submissions for variant NM_002230.4(JUP):c.1035G>C (p.Lys345Asn)

gnomAD frequency: 0.00004  dbSNP: rs150194093

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767065	SCV000235955	uncertain significance	not provided	2014-06-23	criteria provided, single submitter	clinical testing	p.Lys345Asn (AAG>AAC): c.1035 G>C in exon 6 of the JUP gene (NM_002230.2). The K345N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K345N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K345N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in ARVC panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183495	SCV000271859	uncertain significance	not specified	2015-03-05	criteria provided, single submitter	clinical testing	The p.Lys345Asn variant in JUP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 9/67674 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 50194093). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Lys345Asn variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000278374	SCV000402740	uncertain significance	Naxos disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000335744	SCV000402741	uncertain significance	Arrhythmogenic right ventricular dysplasia 12	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705144	SCV000834129	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2023-07-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 155802). This variant has not been reported in the literature in individuals affected with JUP-related conditions. This variant is present in population databases (rs150194093, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 345 of the JUP protein (p.Lys345Asn).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183495	SCV002570931	likely benign	not specified	2022-07-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390299	SCV002698701	likely benign	Cardiovascular phenotype	2022-03-08	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.
Fulgent Genetics, Fulgent Genetics	RCV000705144	SCV002789102	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-11-02	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000143904	SCV000188775	likely benign	Primary familial hypertrophic cardiomyopathy	2013-12-30	no assertion criteria provided	clinical testing