Submissions for variant NM_002230.4(JUP):c.2069A>G (p.Asn690Ser)

gnomAD frequency: 0.00019  dbSNP: rs147628503

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150847	SCV000198397	uncertain significance	not specified	2019-04-12	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV002221461	SCV000235967	uncertain significance	not provided	2024-05-20	criteria provided, single submitter	clinical testing	Identified in a patient with hypertrophic cardiomyopathy and a patient with arrhythmogenic cardiomyopathy (PMID: 32268277, 25351510); Reported in the published literature as possibly associated with autism spectrum disorder, but no additional information was provided (PMID: 25363768); One published functional study suggests the p.(N690S) has no effect on splicing and a second published study utilizing Drosophila mutants showed phenotypes comparable to the reference (PMID: 35051175, 35294868); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34011629, 25351510, 35294868, 35051175, 31133750, 35982159, 32268277, 25363768, 29892012)
Blueprint Genetics	RCV000208373	SCV000263967	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2015-11-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227308	SCV000287311	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 690 of the JUP protein (p.Asn690Ser). This variant is present in population databases (rs147628503, gnomAD 0.02%). 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: 163710). 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.
Illumina Laboratory Services, Illumina	RCV001125575	SCV001284660	uncertain significance	Arrhythmogenic right ventricular dysplasia 12	2018-01-13	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	RCV001125576	SCV001284661	uncertain significance	Naxos disease	2018-01-13	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.
Ambry Genetics	RCV002415637	SCV002727677	likely benign	Cardiovascular phenotype	2022-04-11	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	RCV000227308	SCV002816311	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-09-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149917	SCV003838224	uncertain significance	Cardiomyopathy	2022-02-25	criteria provided, single submitter	clinical testing