ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1717C>T (p.Gln573Ter)
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_001005242.3(PKP2):c.1717C>T (p.Gln573Ter)
Variation ID: 201997 Accession: VCV000201997.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32822589 (GRCh38) [ NCBI UCSC ] 12: 32975523 (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 Jul 5, 2015 Apr 20, 2024 Jun 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1717C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Gln573Ter nonsense NM_004572.4:c.1849C>T NP_004563.2:p.Gln617Ter nonsense NC_000012.12:g.32822589G>A NC_000012.11:g.32975523G>A NG_009000.1:g.79258C>T LRG_398:g.79258C>T LRG_398t1:c.1849C>T LRG_398p1:p.Gln617Ter - Protein change
- Q617*, Q573*
- Other names
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- Canonical SPDI
- NC_000012.12:32822588:G:A
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PKP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1895 | 1948 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (1) |
no assertion criteria provided
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Aug 1, 2011 | RCV000183759.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV003532039.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2023 | RCV003996838.1 |
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
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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
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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
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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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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358872.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study with epicardial cells derived from induced human pluripotent stem cells from a carrier individual has shown that this variant results in the loss of expression of PKP2 in both mRNA and protein levels when compared to the isogenic control cell line generated by targeted gene correction (PMID: 34550725). This variant has been reported in at least two unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 24920660, 25820315, 26850880, 28588093, 32294163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004830234.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study with epicardial cells derived from induced human pluripotent stem cells from a carrier individual has shown that this variant results in the loss of expression of PKP2 in both mRNA and protein levels when compared to the isogenic control cell line generated by targeted gene correction (PMID: 34550725). This variant has been reported in at least two unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 24920660, 25820315, 26850880, 28588093, 32294163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 01, 2011)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280409.1
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gln617Stop (c.1849 C>T) in PKP2 This variant is novel. Since it creates a new stop codon it is predicted to lead to a truncated protein product or no protein product at all, due to nonsense mediated mRNA decay. The majority of pathogenic PKP2 variants are ones that lead to truncated or aberrant protein product (Van Tintelen et al 2006, den Haan et al 2009). Many nonsense variants in PKP2 have been reported in ARVC cases, including one at the neighboring codon (p.Tyr616Stop), which has been reported multiple times in association with ARVC (van Tintelen et al 2006, Bhuiyan et al 2009, Kapplinger et al 2011). Two recent reports at the Heart Rhythm Society meeting noted more severe phenotypes in individuals with PKP2 nonsense (or other null or truncating) variants compared to those with PKP2 missense variants. A recent analysis of rare variants in desmosomal genes in healthy individuals found several PKP2 missense variants but no nonsense variants (Kapplinger et al 2011). These data further support the pathogenic role of nonsense variants in PKP2. This variant has not been reported in dbSNP (as of June 2011). This variant was not seen in the 427 presumably healthy individuals studied by Kapplinger et al (2011). (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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Epicardial differentiation drives fibro-fatty remodeling in arrhythmogenic cardiomyopathy. | Kohela A | Science translational medicine | 2021 | PMID: 34550725 |
Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 Task Force Criteria: clinical performance and simplified practical implementation. | Bosman LP | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2020 | PMID: 32294163 |
Implantable Cardioverter-Defibrillator Therapy in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Predictors of Appropriate Therapy, Outcomes, and Complications. | Orgeron GM | Journal of the American Heart Association | 2017 | PMID: 28588093 |
Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells. | Asimaki A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26850880 |
Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. | Groeneweg JA | Circulation. Cardiovascular genetics | 2015 | PMID: 25820315 |
Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. | Asimaki A | Science translational medicine | 2014 | PMID: 24920660 |
Text-mined citations for rs201405287 ...
HelpRecord last updated Apr 20, 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.