Submissions for variant NM_002230.4(JUP):c.926A>G (p.Asn309Ser)

gnomAD frequency: 0.00010  dbSNP: rs140606359

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171961	SCV000054836	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154727	SCV000204407	uncertain significance	not specified	2013-05-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Asn309Ser varia nt in JUP has not been reported in individuals with cardiomyopathy, but has been identified in 1/8600 European American chromosomes and 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs140606359). Asparagine (Asn) at position 309 is not completely con served in evolutionarily distant species with several (medaka, zebrafish, lampre y, and fruitfly) carrying a serine (Ser; this variant) at this position, suggest ing that this change may be tolerated. Additional computational analyses (bioche mical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that t his variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, the presence of this variant in other species suggests that it is more likely benign, but additional information is needed to fully assess its clinical significance.
Invitae	RCV000467285	SCV000550399	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2022-10-05	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 309 of the JUP protein (p.Asn309Ser). This variant is present in population databases (rs140606359, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 178042). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
GeneDx	RCV000171961	SCV001765169	likely benign	not provided	2019-12-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002372009	SCV002684313	likely benign	Cardiovascular phenotype	2023-02-10	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.