Submissions for variant NM_002230.4(JUP):c.2031G>A (p.Pro677=)

gnomAD frequency: 0.00018  dbSNP: rs188888662

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000126387	SCV000169891	benign	not specified	2014-03-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000126387	SCV000270296	likely benign	not specified	2015-07-30	criteria provided, single submitter	clinical testing	p.Pro677Pro in Exon12 of JUP: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 31/66738 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs188888662).
Ambry Genetics	RCV000619251	SCV000736646	likely benign	Cardiovascular phenotype	2016-06-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001085716	SCV000766959	likely benign	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000645217	SCV001151287	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	JUP: BP4, BP7
Illumina Laboratory Services, Illumina	RCV001127663	SCV001287000	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.
Illumina Laboratory Services, Illumina	RCV001127664	SCV001287001	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170358	SCV001332932	likely benign	Cardiomyopathy	2019-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000126387	SCV001362158	benign	not specified	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: JUP c.2031G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 277244 control chromosomes (gnomAD). The observed variant frequency is approximately 23-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2031G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000126387	SCV001918263	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000645217	SCV001956888	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000645217	SCV001972558	likely benign	not provided		no assertion criteria provided	clinical testing