ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1846C>T (p.Gln616Ter)
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.1846C>T (p.Gln616Ter)
Variation ID: 661424 Accession: VCV000661424.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32974457 (GRCh37) [ NCBI UCSC ] 12: 32821523 (GRCh38) [ 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 Aug 14, 2019 Apr 20, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1846C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Gln616Ter nonsense NM_004572.4:c.1978C>T NP_004563.2:p.Gln660Ter nonsense NC_000012.12:g.32821523G>A NC_000012.11:g.32974457G>A NG_009000.1:g.80324C>T LRG_398:g.80324C>T LRG_398t1:c.1978C>T LRG_398p1:p.Gln660Ter - Protein change
- Q660*, Q616*
- Other names
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- Canonical SPDI
- NC_000012.12:32821522: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 |
1940 | 1993 |
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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Pathogenic (1) |
criteria provided, single submitter
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Jun 2, 2023 | RCV000818836.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2021 | RCV001178375.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV004001815.2 |
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
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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
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000959470.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 661424). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 661424). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563, 29497013). This variant is present in population databases (rs762753884, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln660*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). (less)
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Pathogenic
(Sep 21, 2021)
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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: SCV001342810.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 10 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 10 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563, 24125834) and tachycardia (PMID: 29497013). This variant has been identified in 2/282690 chromosomes 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
(Jan 05, 2024)
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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: SCV004845966.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.1978C>T (p.Gln660*) variant in exon 10 of PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to result … (more)
The c.1978C>T (p.Gln660*) variant in exon 10 of PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to result in an absent or truncated protein product. This variant has been reported in at least 5 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20152563, 24125834, 34469894, 30699244) and in an individual with complex tachycardia (PMID: 29497013). Loss-of-function variants in the PKP2 gene are known to be pathogenic (ClinGen dosage sensitivity score 3, PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss-of-function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC (PMID: 23354045, 24967631, 25971409, 26590176) and classified as pathogenic by several submitters in ClinVar (ID: 45054, 202022). This variant is rare (2/282690; 0.000007075) in the general population database gnomAD and classified as pathogenic in ClinVar submitters (ID: 661424). Therefore, the c.1978C>T (p.Gln660*) variant in the PKP2 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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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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Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers. | Svensson A | Cardiology | 2021 | PMID: 34469894 |
The genetic architecture of Plakophilin 2 cardiomyopathy. | Dries AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34120153 |
Characteristics of recurrent ventricular tachyarrhythmia after catheter ablation in patients with arrhythmogenic right ventricular cardiomyopathy. | Lin CY | Journal of cardiovascular electrophysiology | 2019 | PMID: 30699244 |
Genetic basis of channelopathies and cardiomyopathies in Hong Kong Chinese patients: a 10-year regional laboratory experience. | Mak CM | Hong Kong medical journal = Xianggang yi xue za zhi | 2018 | PMID: 29497013 |
Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients. | Pilichou K | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 29038103 |
Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. | Sommariva E | European heart journal | 2016 | PMID: 26590176 |
Maturation-Based Model of Arrhythmogenic Right Ventricular Dysplasia Using Patient-Specific Induced Pluripotent Stem Cells. | Wen JY | Circulation journal : official journal of the Japanese Circulation Society | 2015 | PMID: 25971409 |
Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy. | Alcalde M | PloS one | 2014 | PMID: 24967631 |
Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. | Rasmussen TB | Circulation. Cardiovascular genetics | 2014 | PMID: 24704780 |
Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy. | Bao J | Circulation. Cardiovascular genetics | 2013 | PMID: 24125834 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. | Kim C | Nature | 2013 | PMID: 23354045 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. | Gerull B | Nature genetics | 2004 | PMID: 15489853 |
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Text-mined citations for rs762753884 ...
HelpRecord last updated Sep 29, 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.