ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter)
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.1780C>T (p.Gln594Ter)
Variation ID: 45049 Accession: VCV000045049.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32822526 (GRCh38) [ NCBI UCSC ] 12: 32975460 (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 Jun 1, 2016 Oct 8, 2024 Jul 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1780C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Gln594Ter nonsense NM_004572.4:c.1912C>T NP_004563.2:p.Gln638Ter nonsense NC_000012.12:g.32822526G>A NC_000012.11:g.32975460G>A NG_009000.1:g.79321C>T LRG_398:g.79321C>T LRG_398t1:c.1912C>T LRG_398p1:p.Gln638Ter - Protein change
- Q638*, Q594*
- Other names
- p.Q638*:CAG>TAG
- Canonical SPDI
- NC_000012.12:32822525: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 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
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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 |
1941 | 1994 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2024 | RCV000183763.30 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2023 | RCV000211841.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000531123.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2023 | RCV001188338.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2020 | RCV001175485.3 |
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
(May 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated arrhythmogenic right ventricular dysplasia
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740392.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
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Pathogenic
(Mar 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia/cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339078.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PKP2 c.1912C>T (p.Gln638X) 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.1912C>T (p.Gln638X) 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 252142 control chromosomes. c.1912C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Gerull_2004, Wlodarska_2008, Perrin_2013, Alcalde_2014, Adler_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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
(Sep 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: SCV002810506.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 21, 2022)
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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: SCV004239574.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 10, 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: SCV001355375.3
First in ClinVar: Jun 22, 2020 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. This variant has been reported in over 30 individuals from multiple families affected with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 23810883, 24967631, 26743238). This variant has been identified in 2/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 19, 2024)
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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: SCV000638874.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln638*) 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.Gln638*) 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, 17041889, 23911551). This variant is present in population databases (rs397517012, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (PMID: 15489853, 23810883, 24967631, 26743238). ClinVar contains an entry for this variant (Variation ID: 45049). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 14, 2020)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV005045692.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
The c.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent … (more)
The c.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in multiple individuals (>15) affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) (PMID:23810883, 15489853, 24967631). Loss of function variants are known to be pathogenic for PKP2 (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:15489853, 28431057, 30790397) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 201998). This variant was found to be rare (2/282710; 0.0007%) in the general population database gnomAD and classified as pathogenic by multiple ClinVar submitters (ClinVar ID: 45049). Therefore, the c.1912C>T (p.Gln638*) variant in PKP2 gene is classified as pathogenic. (less)
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Pathogenic
(Jul 11, 2024)
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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: SCV000236244.16
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense 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: 25525159, 23810883, 26743238, 30790397, 31737537, 30731207, 32268277, 32372669, 31402444, 31386562, 15489853, 35819174, 24967631, 35653365, 34120153) (less)
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Pathogenic
(Jun 22, 2010)
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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: SCV000061856.6
First in ClinVar: May 03, 2013 Last updated: Sep 22, 2018 |
Comment:
The Gln638X variant has been reported in one individual who presented with synco pe, right ventricular involvement, and ventricular tachycardia (Gerull et al, 20 05). … (more)
The Gln638X variant has been reported in one individual who presented with synco pe, right ventricular involvement, and ventricular tachycardia (Gerull et al, 20 05). In addition, the Gln638X variant leads to a premature stop at codon 638. T his alteration is predicted to lead to a truncated or absent protein. Loss of fu nction variants are an established mechanism of disease for the PKP2 gene, which makes it highly likely that the Gln638X variant is pathogenic. (less)
Number of individuals with the variant: 5
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Pathogenic
(Oct 02, 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: SCV004845970.1
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.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent … (more)
The c.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in multiple individuals (>15) affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) (PMID:23810883, 15489853, 24967631). Loss of function variants are known to be pathogenic for PKP2 (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:15489853, 28431057, 30790397) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 201998). This variant was found to be rare (2/282710; 0.0007%) in the general population database gnomAD and classified as pathogenic by multiple ClinVar submitters (ClinVar ID: 45049). Therefore, the c.1912C>T (p.Gln638*) variant in PKP2 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2020)
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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: SCV001501411.22
First in ClinVar: Mar 14, 2021 Last updated: Oct 08, 2024 |
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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The genetic architecture of Plakophilin 2 cardiomyopathy. | Dries AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34120153 |
High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Hermida A | European journal of heart failure | 2019 | PMID: 30790397 |
Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients. | Pilichou K | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 29038103 |
Quantitative analysis of PKP2 and neighbouring genes in a patient with arrhythmogenic right ventricular cardiomyopathy caused by heterozygous PKP2 deletion. | Sonoda K | 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 | 2017 | PMID: 28431057 |
Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. | Perrin MJ | Journal of the American College of Cardiology | 2013 | PMID: 23810883 |
Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Awad MM | Nature clinical practice. Cardiovascular medicine | 2008 | PMID: 18382419 |
Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. | Awad MM | Human mutation | 2006 | PMID: 17041889 |
Genetics of right ventricular cardiomyopathy. | Sen-Chowdhry S | Journal of cardiovascular electrophysiology | 2005 | PMID: 16101641 |
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 rs397517012 ...
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.