ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1211dup (p.Val406fs)
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.1211dup (p.Val406fs)
Variation ID: 45015 Accession: VCV000045015.38
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32850932-32850933 (GRCh38) [ NCBI UCSC ] 12: 33003866-33003867 (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 Feb 24, 2015 Oct 8, 2024 Sep 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1211dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Val406fs frameshift NM_004572.3:c.1211dupT NM_004572.4:c.1211dup NP_004563.2:p.Val406fs frameshift NC_000012.12:g.32850933dup NC_000012.11:g.33003867dup NG_009000.1:g.50914dup LRG_398:g.50914dup LRG_398t1:c.1211dup LRG_398p1:p.Val406fs - Protein change
- V406fs
- Other names
- p.Val406fs
- Canonical SPDI
- NC_000012.12:32850932: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
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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 |
1940 | 1993 |
Conditions - Germline
Condition
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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 (1) |
criteria provided, single submitter
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Jan 18, 2019 | RCV000038154.14 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2023 | RCV000603676.22 | |
Pathogenic (4) |
criteria provided, single submitter
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Nov 1, 2022 | RCV001699188.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2017 | RCV001841581.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2023 | RCV002354195.10 |
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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Pathogenic
(Sep 27, 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: SCV000959255.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val406Serfs*4) in the PKP2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Val406Serfs*4) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with arrhythmogenic rightventricular dysplasia/cardiomyopathy and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16567567, 23871674, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as 1211–1212insT (Val406SerfsX3) and c.1211dup p.(Val406fs). ClinVar contains an entry for this variant (Variation ID: 45015). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920004.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The PKP2 c.1211dupT (p.Val406SerfsX4) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense … (more)
Variant summary: The PKP2 c.1211dupT (p.Val406SerfsX4) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 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 (e.g. c.1613G>A/ p.Trp538X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246050 control chromosomes. This variant has been reported in multiple confirmed ARVD patients, some of whom have a strong family history. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 28, 2021)
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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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MGZ Medical Genetics Center
Accession: SCV002580541.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM2_SUP, PP1
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Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Mar 29, 2023)
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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: SCV002653355.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1211dupT pathogenic mutation, located in coding exon 5 of the PKP2 gene, results from a duplication of T at nucleotide position 1211, causing a … (more)
The c.1211dupT pathogenic mutation, located in coding exon 5 of the PKP2 gene, results from a duplication of T at nucleotide position 1211, causing a translational frameshift with a predicted alternate stop codon (p.V406Sfs*4). This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 21, 2015)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744702.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Jan 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061820.5
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Val406SerfsX4 variant in PKP2 has been identified in >15 individuals with ARVC, the majority of whom were Dutch (van Tintelen 2006, Groeneweg 2013, Orgero … (more)
The p.Val406SerfsX4 variant in PKP2 has been identified in >15 individuals with ARVC, the majority of whom were Dutch (van Tintelen 2006, Groeneweg 2013, Orgero n 2017, Proost 2017, Walsh 2017, LMM data). It was also identified in the homozy gous state in 2 siblings with hypoplastic left heart syndrome (Verhagen 2018). I t was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 406 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of f unction of the PKP2 gene is an established disease mechanism in autosomal domina nt ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP criteria applied: PVS1, PS4, PM2. (less)
Number of individuals with the variant: 11
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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821690.13
First in ClinVar: Jan 21, 2023 Last updated: Oct 08, 2024 |
Comment:
PKP2: PVS1, PM2
Number of individuals with the variant: 1
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926794.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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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: SCV000733163.1 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: SCV001918289.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 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: SCV001958211.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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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Homozygous Truncating Variant in PKP2 Causes Hypoplastic Left Heart Syndrome. | Verhagen JMA | Circulation. Genomic and precision medicine | 2018 | PMID: 30562116 |
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 |
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
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 |
The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. | De Bortoli M | European journal of human genetics : EJHG | 2010 | PMID: 20197793 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study. | Bhuiyan ZA | Circulation. Cardiovascular genetics | 2009 | PMID: 20031616 |
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 rs397516989 ...
HelpRecord last updated Oct 08, 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.