ClinVar Genomic variation as it relates to human health
NM_002230.4(JUP):c.389TCA[1] (p.Ile131del)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002230.4(JUP):c.389TCA[1] (p.Ile131del)
Variation ID: 402991 Accession: VCV000402991.15
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 17q21.2 17: 41769492-41769494 (GRCh38) [ NCBI UCSC ] 17: 39925744-39925746 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 9, 2017 Aug 11, 2024 Mar 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002230.4:c.389TCA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002221.1:p.Ile131del inframe deletion NM_002230.4:c.392_394del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001352773.2:c.389TCA[1] NP_001339702.1:p.Ile131del inframe deletion NM_001352774.2:c.389TCA[1] NP_001339703.1:p.Ile131del inframe deletion NM_001352775.2:c.389TCA[1] NP_001339704.1:p.Ile131del inframe deletion NM_001352776.2:c.389TCA[1] NP_001339705.1:p.Ile131del inframe deletion NM_001352777.2:c.389TCA[1] NP_001339706.1:p.Ile131del inframe deletion NM_021991.4:c.389TCA[1] NP_068831.1:p.Ile131del inframe deletion NC_000017.11:g.41769492TGA[1] NC_000017.10:g.39925744TGA[1] NG_009090.2:g.22216TCA[1] LRG_401:g.22216TCA[1] LRG_401t1:c.392_394del LRG_401t2:c.392_394del - Protein change
- I131del
- Other names
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- Canonical SPDI
- NC_000017.11:41769491:TGATGA:TGA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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JUP | - | - |
GRCh38 GRCh37 |
1180 | 1198 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Oct 20, 2016 | RCV000455097.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 18, 2024 | RCV000619988.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000645204.6 | |
Uncertain significance (1) |
no assertion criteria provided
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Nov 1, 2017 | RCV000786329.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539413.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
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 … (more)
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) (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 12
Naxos disease
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000766946.4
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
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. … (more)
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. (less)
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Uncertain significance
(Mar 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000735421.6
First in ClinVar: Apr 14, 2018 Last updated: Aug 11, 2024 |
Comment:
The c.392_394delTCA variant (also known as p.I131del) is located in coding exon 2 of the JUP gene. This variant results from an in-frame TCA deletion … (more)
The c.392_394delTCA variant (also known as p.I131del) is located in coding exon 2 of the JUP gene. This variant results from an in-frame TCA deletion at nucleotide positions 392 to 394. This results in the in-frame deletion of an isoleucine at codon 131. This variant has been reported in an arrhythmogenic right ventricular cardiomyopathy cohort, but clinical details were limited (Xu T et al, J. Am. Coll. Cardiol. 2010 Feb; 55(6):587-97). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Naxos disease
Arrhythmogenic right ventricular dysplasia 12
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782466.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 12
Naxos disease
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925263.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Atrial fibrillation (present)
Secondary finding: no
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Uncertain significance
(Nov 01, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925104.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
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 … (more)
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). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Text-mined citations for rs781818082 ...
HelpRecord last updated Aug 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.