rs781818082

chr17-41769491-TTGA-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_002230.4(JUP):c.392_394del(p.Ile131del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: JUP NM_002230.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 9.31

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002230.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4	c.392_394del	p.Ile131del	inframe_deletion	3/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.392_394del	p.Ile131del	inframe_deletion	3/14	1	NM_002230.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247702 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460936 Hom.: 0 AF XY: 0.0000193 AC XY: 14 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This variant, c.392_394del, results in the deletion of 1 amino acid(s) of the JUP protein (p.Ile131del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs781818082, gnomAD 0.0009%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 402991). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 12, 2022	The c.392_394del variant identified in the JUP gene is predicted to result in deletion of one amino acid [p.(Ile131del)] without causing a shift in the reading frame (in-frame deletion). This variant is observed in 12 individuals across population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. This variant has been identified in one individual affected with arrhythmogenic right ventricular cardiomyopathy [PMID: 20152563], and has also been reported four times in ClinVar as a Variant of Uncertain Significance (ClinVarID:402991). In silico predictions are not available for this variant. Based on the available evidence, the c.392_394del p.(Ile131del) variant identified in the JUP gene is reported as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with ARVC (PMID 20152563) -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 01, 2017

p.Ile131del (c.392_394delTCA) in exon 3 of the JUP gene (NM_002230.2; chr17-39925744-TGA-) SCICD Classification: variant of uncertain significance based on sparse case data and lack of functional data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: JUP: JUP encodes plakoglobin, an integral protein in the desmosome. Disruption in the desmosome results in cardiomyocytes that are partciularly sensitive to mechanical stress. Pathogenic variants in JUP are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and Naxos disease, an autosomal recessive disease with a cardio-cutaneous phenotype. Two other variants in ClinVar with in-frame dels or dups of one amino acid: -One classified as pathogenic: Asimaki et al. (2007) identified a heterozygous 3-bp insertion (118_119GCA) in the plakoglobin gene predicted to insert an extra serine residue at position 39 in the N terminus of the protein (S39_K40insS). -One classified as VUS by Illumina, with no clinical data. Missense and loss of function variants in JUP are more prevalent in cases of cardiomyopathy vs. Controls (OR=7.8 for missense variants; OR=28.1 for loss of function variants). This variant is located in the helix domain of plakoglobin. Amino acid 131 is very close to an armadillo (ARM) domain (position 132-171), which is sufficient for binding other desmosomal proteins like DSG1 and this first ARM domain associated with CTNNA1. Association with DSC1 requires both ends of the ARM domain to be present. Deletion of amino acid isoleucine at position 131 may shift the position of these structural domains; however, this has not been proven with functional studies (http://www.uniprot.org/uniprot/P14923; Choi et al 2009) Case data (not including our patient): 2 · ClinVar: submitted by 1 lab · Laboratory for Molecular Medicine: seen in 1 patient referred for whole genome/exome sequencing. Per Meg Crawley at LMM: this variant was seen on a research basis from an outside hospital and they did not receive any clinical information for the project. They classified it as a VUS and did not report it out. · Xu et al 2011: This variant was seen in 1 out of 198 patients with ARVC referred for genetic testing. Emailed author for clinical details. Segregation data: none reported. emailed author for details Functional data: none reported Conservation data: The isoleucine at codon 131 is completely conserved across species. Neighboring amino acids are also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 121,388 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 1 of 55,061 individuals of European descent (MAF=0.0009%). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2016

The c.392_394delTCA (p.I131del) alteration is located in exon 3 (coding exon 2) of the JUP gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.392 and c.394, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781818082; hg19: chr17-39925743;