Submissions for variant NM_002230.4(JUP):c.509C>T (p.Ser170Leu)

gnomAD frequency: 0.00003  dbSNP: rs782284038

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588554	SCV000235946	uncertain significance	not provided	2018-08-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the JUP gene. The S170L variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for arrhythmia genetic testing at GeneDx, although this individual harbored additional cardiogenetic variants and no segregation data are available. This variant is also observed at a global allele frequency of 11/267372 (0.004%) alleles in large population cohorts, including 7/124788 (0.006%) alleles from individuals of European (non-Finnish) ancestry (Lek et al., 2016). The S170L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Illumina Laboratory Services, Illumina	RCV000321164	SCV000402752	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.
Illumina Laboratory Services, Illumina	RCV000378103	SCV000402753	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541609	SCV000645742	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 170 of the JUP protein (p.Ser170Leu). This variant is present in population databases (rs794729034, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 201812). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175368	SCV000699466	uncertain significance	not specified	2025-01-13	criteria provided, single submitter	clinical testing	Variant summary: JUP c.509C>T (p.Ser170Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 241372 control chromosomes (gnomAD v2.1). Variant occurrences in several carriers suggest that this variant is likely not associated with a high penetrance, severe, early onset disease phenotype in heterozygous state, however association with an autosomal recessive phenotype (e.g. Naxos Disease), cannot be excluded based on these data. The variant, c.509C>T, has been reported in the literature in the presumed heterozygous state in at least 1 individual affected with dilated cardiomyopathy (example, Mazzarotto_2020), however the full genotype/phenotype information was not available. These report(s) do not provide unequivocal conclusions about association of the variant with JUP-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 201812). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002336467	SCV002644606	likely benign	Cardiovascular phenotype	2023-02-08	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.
PreventionGenetics, part of Exact Sciences	RCV003416106	SCV004113337	uncertain significance	JUP-related disorder	2023-10-06	criteria provided, single submitter	clinical testing	The JUP c.509C>T variant is predicted to result in the amino acid substitution p.Ser170Leu. This variant was reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-39925419-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.