Submissions for variant NM_002230.4(JUP):c.950A>T (p.Gln317Leu)

gnomAD frequency: 0.00001  dbSNP: rs782509792

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192708	SCV001361000	uncertain significance	not specified	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: JUP c.950A>T (p.Gln317Leu) results in a non-conservative amino acid change located in one of the Armadillo domain (IPR000225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251442 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.950A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported [TTR c.424G>A (p.Val142Ile)]in an internal sample, providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001876249	SCV002194383	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2022-06-13	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 928584). This variant has not been reported in the literature in individuals affected with JUP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 317 of the JUP protein (p.Gln317Leu).
Ambry Genetics	RCV002375118	SCV002685454	likely benign	Cardiovascular phenotype	2023-02-27	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.
GeneDx	RCV002473214	SCV002770188	uncertain significance	not provided	2022-12-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function