ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1689dup (p.Val564fs)
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.1689dup (p.Val564fs)
Variation ID: 45047 Accession: VCV000045047.20
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32822616-32822617 (GRCh38) [ NCBI UCSC ] 12: 32975550-32975551 (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 Oct 2, 2016 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1689dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Val564fs frameshift NM_001005242.3:c.1689dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004572.3:c.1821dupT NM_004572.4:c.1821dup NP_004563.2:p.Val608fs frameshift NC_000012.12:g.32822617dup NC_000012.11:g.32975551dup NG_009000.1:g.79230dup LRG_398:g.79230dup LRG_398t1:c.1821dup LRG_398p1:p.Val608fs - Protein change
- V608fs, V564fs
- Other names
- p.Val608CysfsX6
- Canonical SPDI
- NC_000012.12:32822616:A:AA
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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
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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PKP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1774 | 1827 |
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000038187.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2016 | RCV000242219.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 3, 2021 | RCV000640015.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2022 | RCV001008767.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2019 | RCV001171163.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 31, 2022 | RCV002265578.1 |
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
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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Likely pathogenic
(Mar 14, 2019)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333848.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated arrhythmogenic right ventricular dysplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548331.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: PKP2 c.1821dupT (p.Val608CysfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PKP2 c.1821dupT (p.Val608CysfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251212 control chromosomes. c.1821dupT has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Bhonsale_2013, te Riele_2016, DeWitt_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 01, 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: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812561.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in PKP2 is a frameshift variant predicted to cause a premature stop codon, p.(Val564Cysfs*6), in biologically relevant exon 8/14 leading to nonsense-mediated … (more)
This sequence change in PKP2 is a frameshift variant predicted to cause a premature stop codon, p.(Val564Cysfs*6), in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0009% (10/1,111,944 alleles) in the European (non-Finnish) population. This variant has been reported in at least four unrelated probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy and segregates with disease in at least two families (PMID: 31319917, 28588093, 34469894). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PP1, PS4_Supporting (less)
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Likely pathogenic
(Apr 25, 2018)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840043.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene has not been reported previously while observed with extremely low allele frequency in general population according to … (more)
This c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene has not been reported previously while observed with extremely low allele frequency in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene is classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061854.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Val608fs variant in PKP2 has been reported in 2 individuals with clinical features of ARVC (Bhonsale 2013, LMM unpublished data). This variant has been … (more)
The p.Val608fs variant in PKP2 has been reported in 2 individuals with clinical features of ARVC (Bhonsale 2013, LMM unpublished data). This variant has been id entified in 1/111470 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517010) and has been previ ously reported in ClinVar (Variation ID 45047). This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 608 and leads to a premature termination codon 6 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Val608fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_S (Richards 2015). (less)
Number of individuals with the variant: 3
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Pathogenic
(Jan 02, 2016)
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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: SCV000320675.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.1821dupT pathogenic mutation, located in coding exon 9 of the PKP2 gene, results from a duplication of T at nucleotide position 1821, causing a … (more)
The c.1821dupT pathogenic mutation, located in coding exon 9 of the PKP2 gene, results from a duplication of T at nucleotide position 1821, causing a translational frameshift with a predicted alternate stop codon (p.V608Cfs*6). This alteration has been reported in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6(3):569-78; Bhonsale A et al. Eur Heart J. 2015;36(14):847-55; Groeneweg JA et al. Circ Cardiovasc Genet. 2015;8(3):437-46; te Riele AS et al. JACC: Clinical Electrophysiology. 2015;1(6):551-60). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001168555.3
First in ClinVar: Mar 16, 2020 Last updated: Dec 17, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25616645, 34120153, 23671136, 26314686, 25820315, 28588093, 31402444, 31447099, 31386562, 35536239, 31319917) (less)
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Pathogenic
(Aug 03, 2021)
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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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Invitae
Accession: SCV000761602.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant has … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28588093, Invitae). ClinVar contains an entry for this variant (Variation ID: 45047). This variant is present in population databases (rs397517010, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Val608Cysfs*6) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. (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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Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers. | Svensson A | Cardiology | 2021 | PMID: 34469894 |
Phenotypic Manifestations of Arrhythmogenic Cardiomyopathy in Children and Adolescents. | DeWitt ES | Journal of the American College of Cardiology | 2019 | PMID: 31319917 |
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 |
Approach to family screening in arrhythmogenic right ventricular dysplasia/cardiomyopathy. | te Riele AS | European heart journal | 2016 | PMID: 26314686 |
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 |
Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. | Bhonsale A | European heart journal | 2015 | PMID: 25616645 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | Bhonsale A | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23671136 |
Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. | Gerull B | Nature genetics | 2004 | PMID: 15489853 |
Text-mined citations for rs397517010 ...
HelpRecord last updated Apr 15, 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.