ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.2254T>C (p.Cys752Arg)
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.2254T>C (p.Cys752Arg)
Variation ID: 201965 Accession: VCV000201965.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32796212 (GRCh38) [ NCBI UCSC ] 12: 32949146 (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 Mar 8, 2017 Feb 20, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.2254T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Cys752Arg missense NM_004572.4:c.2386T>C NP_004563.2:p.Cys796Arg missense NC_000012.12:g.32796212A>G NC_000012.11:g.32949146A>G NG_009000.1:g.105635T>C LRG_398:g.105635T>C LRG_398t1:c.2386T>C LRG_398p1:p.Cys796Arg Q99959:p.Cys796Arg - Protein change
- C796R, C752R
- Other names
- p.C796R:TGT>CGT
- Canonical SPDI
- NC_000012.12:32796211:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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 |
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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Pathogenic (4) |
criteria provided, single submitter
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Sep 15, 2023 | RCV000183710.11 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2023 | RCV000456556.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003165405.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2023 | RCV003114339.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2023 | RCV003486740.1 |
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
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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Pathogenic
(Oct 08, 2014)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743446.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(Sep 15, 2023)
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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: SCV000236188.14
First in ClinVar: Jul 05, 2015 Last updated: Sep 22, 2023 |
Comment:
A functional study examining both in vitro and in vivo effects of the p.(C796R) variant demonstrated protein instability and degradation via calpain proteases, suggesting haploinsufficiency … (more)
A functional study examining both in vitro and in vivo effects of the p.(C796R) variant demonstrated protein instability and degradation via calpain proteases, suggesting haploinsufficiency as the mechanism of disease (Kirchner et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34120153, 15489853, 23889974, 21553091, 26082552, 21636032, 23147395, 26585103, 29456632, 28492532, 23863954, 31737537, 30847666, 31386562, 31402444, 23871674, 25820315, 33662488, 21606396, 22781308, 34469894, 23085127, 16567567) (less)
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Pathogenic
(Nov 09, 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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Invitae
Accession: SCV000545219.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 796 of the PKP2 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 796 of the PKP2 protein (p.Cys796Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 21636032, 23871674). It is commonly reported in individuals of Dutch ancestry (PMID: 21636032, 23871674). ClinVar contains an entry for this variant (Variation ID: 201965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PKP2 function (PMID: 22781308, 23863954). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 20, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813853.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 16, 2023)
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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: SCV003800977.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: PKP2 c.2386T>C (p.Cys796Arg) results in a non-conservative amino acid change located in the armadillo domain (Kirchner_2012) of the encoded protein sequence. Four of … (more)
Variant summary: PKP2 c.2386T>C (p.Cys796Arg) results in a non-conservative amino acid change located in the armadillo domain (Kirchner_2012) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.2386T>C has been reported in the literature in numerous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and has been reported as a Dutch founder mutation (eg. Kirchner_2012, Cox_2011, Groeneweg_2015, etc). In vitro expression studies demonstrated that the the variant leads to protein instability and degradation involving calpain proteases as well as affecting protein folding, and altering the normal cell membrane localization (Kirchner_2012, Gerull_2013). Three 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 21, 2022)
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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: SCV003866305.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.C796R pathogenic mutation (also known as c.2386T>C), located in coding exon 12 of the PKP2 gene, results from a T to C substitution at … (more)
The p.C796R pathogenic mutation (also known as c.2386T>C), located in coding exon 12 of the PKP2 gene, results from a T to C substitution at nucleotide position 2386. The cysteine at codon 796 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), noting it as a founder mutation in the Dutch population (Gerull B et al. Nat Genet, 2004 Nov;36:1162-4; van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Campian ME et al. Eur J Nucl Med Mol Imaging, 2010 Nov;37:2079-85; Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11; Noorman M et al. Heart Rhythm, 2013 Feb;10:283-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Svensson A et al. Cardiology, 2021 Sep;146:763-771). Additionally, an in vitro study showed this alteration leads to protein instability and degradation (Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 05, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239575.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733155.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921728.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951749.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970519.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
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 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers. | Groeneweg JA | The American journal of cardiology | 2013 | PMID: 23871674 |
Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. | Gerull B | Circulation. Cardiovascular genetics | 2013 | PMID: 23863954 |
End stage of arrhythmogenic cardiomyopathy with severe involvement of the interventricular septum. | Noorman M | Heart rhythm | 2013 | PMID: 23085127 |
Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations. | Kirchner F | Circulation. Cardiovascular genetics | 2012 | PMID: 22781308 |
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. | Kapplinger JD | Journal of the American College of Cardiology | 2011 | PMID: 21636032 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. | Cox MG | Circulation | 2011 | PMID: 21606396 |
Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Campian ME | European journal of nuclear medicine and molecular imaging | 2010 | PMID: 20603720 |
Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. | van Tintelen JP | Circulation | 2006 | PMID: 16567567 |
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 rs794729098 ...
HelpRecord last updated Feb 28, 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.