Submissions for variant NM_002230.4(JUP):c.427G>A (p.Ala143Thr)

gnomAD frequency: 0.00007  dbSNP: rs375788626

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183485	SCV000271862	uncertain significance	not specified	2017-09-04	criteria provided, single submitter	clinical testing	The p.Ala143Thr variant in JUP has been reported in 2 individuals with ARVC (LaG erche 2010; Green 2015). It has been also identified in 4/18780 of East Asian ch romosomes and 15/124482 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375788626). Computational pre diction tools and conservation analysis suggest that the p.Ala143Thr variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Ala143Thr varia nt is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471931	SCV000550408	benign	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326992	SCV002631759	likely benign	Cardiovascular phenotype	2023-05-19	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.
Fulgent Genetics, Fulgent Genetics	RCV000471931	SCV002778371	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2021-08-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150061	SCV003838891	uncertain significance	Cardiomyopathy	2021-08-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786327	SCV004811102	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786327	SCV000925102	uncertain significance	not provided	2017-06-26	no assertion criteria provided	provider interpretation	p.Ala143Thr (c.427G>A) in exon 3 of the JUP gene (NM_002230.2) Given that variants in this gene are not strongly associated with HCM and that this variant has been seen at a relatively high frequency in the general population, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 4 unrelated cases of ARVC (not including this patient's family). The case data is weak. This variant is present in ClinVar and is classified as a variant of uncertain significance. It is also classified as a variant of uncertain significance by the Laboratory for Molecular Medicine. LMM has seen it in 1 individual. This variant was reported in 2 of 27 individuals with ARVC (Green et al 2015). The purpose of this study was to design and validate an NGS test panel for ARVC. It was also present in 1 out of 47 athletes with an ARVC phenotype (La Gerche et al 2010). Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." The alanine at codon 143 is completely conserved across species. No other variants have been reported in association with disease at this codon. The variant was reported online in 24 of 136,360 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 9,390 individuals of East Asian descent (MAF=0.02%), 15 of 62,241 individuals of European descent, 2 of 12,393 individuals of Finnish descent, 2 of 17,104 individuals of Latino descent and 1 of 3,189 individuals of other descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.