Submissions for variant NM_002230.4(JUP):c.567C>T (p.Val189=)

gnomAD frequency: 0.00090  dbSNP: rs35297577

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039085	SCV000062763	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Val189Val in Exon 04 of JUP: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence. It has been identified in 0.2% (7/3734) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs35297577).
GeneDx	RCV000039085	SCV000168905	benign	not specified	2014-03-10	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.
Ambry Genetics	RCV000251291	SCV000317826	likely benign	Cardiovascular phenotype	2018-01-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084270	SCV000560972	benign	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000463501	SCV001151300	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	JUP: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039085	SCV001362160	benign	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: JUP c.567C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 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 0.0003 in 247354 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 104 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Cardiomyopathy phenotype (2.5e-05), strongly 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.567C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile) at our laboratory providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Phosphorus, Inc.	RCV000039085	SCV002073393	likely benign	not specified	2022-01-13	criteria provided, single submitter	clinical testing	This synonymous variant has occurred in GnomAD with a total MAF of 0.0305% and with the highest MAF of 0.2576% in the African population. This position is not conserved. In silico splicing algorithm predicted no impact on splicing, but no functional studies were performed to confirm this prediction. This variant NM_002230.4(JUP):c.567C>T (p.Val189=) is present in the ClinVar database (ID: 45854). The variant has not occurred in the literature in association with the disease. Considering that the variant has a relatively high frequency in a subpopulation, it has been classified as Likely Benign.
Clinical Genetics, Academic Medical Center	RCV000039085	SCV001918166	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000463501	SCV001973699	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754284	SCV005353908	likely benign	JUP-related disorder	2024-04-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).