ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.2014-1G>C
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.2014-1G>C
Variation ID: 6756 Accession: VCV000006756.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32802557 (GRCh38) [ NCBI UCSC ] 12: 32955491 (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 Apr 4, 2013 Apr 15, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.2014-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001407155.1:c.2014-1G>C splice acceptor NM_001407156.1:c.1849-1G>C splice acceptor NM_001407158.1:c.1687-1G>C splice acceptor NM_001407159.1:c.1687-1G>C splice acceptor NM_001407160.1:c.1687-1G>C splice acceptor NM_004572.4:c.2146-1G>C splice acceptor NC_000012.12:g.32802557C>G NC_000012.11:g.32955491C>G NG_009000.1:g.99290G>C LRG_398:g.99290G>C LRG_398t1:c.2146-1G>C - Protein change
- Other names
- IVS10, G-C, -1
- Canonical SPDI
- NC_000012.12:32802556:C: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (20) |
criteria provided, multiple submitters, no conflicts
|
Jan 20, 2024 | RCV000007148.37 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 26, 2019 | RCV000054811.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2022 | RCV000252055.4 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000183771.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2023 | RCV000771879.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV003924809.1 |
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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Pathogenic
(Nov 09, 2017)
|
criteria provided, single submitter
Method: research
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000677114.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Number of individuals with the variant: 1
|
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Pathogenic
(Oct 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743451.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(Oct 10, 2017)
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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
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061868.6
First in ClinVar: May 03, 2013 Last updated: Sep 22, 2018 |
Comment:
The c.2146-1G>C variant in PKP2 has been reported in >30 individuals with ARVC ( Gerull 2004, Syrris 2006, Dalal 2006, Wlodarska 2008, Watkins 2009, den … (more)
The c.2146-1G>C variant in PKP2 has been reported in >30 individuals with ARVC ( Gerull 2004, Syrris 2006, Dalal 2006, Wlodarska 2008, Watkins 2009, den Haan 200 9, Asimaki 2009, La Gerche 2010, Fressart 2010, Borahona-Dussault 2010, Cox 2011 , Baskin 2013, Philips 2014, Svensson 2016, Walsh 2017, LMM data, ClinVar Variat ion ID: 6756) and segregated with disease in at least 8 affected relatives from 5 families (Groeneweg 2014, Svensson 2016, LMM data). However, it has also been observed in multiple unaffected individuals over the age of 50, which suggests t hat penetrance may be reduced (Perrin 2013, Svensson 2016, LMM data). In additio n, this variant has been identified in 10/126558 European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1939 22674). Please note that for diseases with clinical variability or reduced penet rance, pathogenic variants may be present at a low frequency in the general popu lation. The c.2146-1G>C variant has been shown to cause skipping of exon 11, res ulting in a frameshift (p.Pro716fs) and premature termination 32 amino acids dow nstream, ultimately leading to a marked reduction of PKP2 protein in the myocard ium (Gerull 2004, Asimaki 2009, Groeneweg 2014). Heterozygous loss of PKP2 funct ion is an established disease mechanism in individuals with ARVC. In summary, th is variant meets criteria to be classified as pathogenic for ARVC in an autosoma l dominant manner; however, it should be noted that penetrance may be reduced. A CMG/AMP Criteria applied: PVS1, PS4, PM2, PP1_Moderate (Richards 2015). (less)
Number of individuals with the variant: 35
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Pathogenic
(Sep 21, 2018)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993586.1 First in ClinVar: Sep 24, 2019 Last updated: Sep 24, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053029.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 08, 2019 |
Comment:
Variant summary: PKP2 c.2146-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: PKP2 c.2146-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing, specifically that the variant abolishes a 3' acceptor site. This prediction was confirmed by experimental evidence that demonstrated this variant affects mRNA splicing resulting in exon 11 skipping (Gerull_2004, Groeneweg_2014). The variant allele was found at a frequency of 3.2e-05 in 251262 control chromosomes (gnomAD). c.2146-1G>C has been reported in the literature in numerous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, including unrelated families where the variant co-segregated with the disease, though incomplete co-segregation was also observed suggesting somewhat reduced penetrance (Dalal_2006, Fressart_2010, Gerull_2004, Groeneweg_2014, Syrris_2006). These data indicate that the variant is very likely to be associated with disease. Immunohistochemical studies indicated marked reduction of the PKP2 protein level in a myocardium sample from an affected individual (Asimaki_2009). 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 08, 2017)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000996364.2
First in ClinVar: Nov 02, 2019 Last updated: Jan 09, 2020 |
Comment:
The PKP2 c.2146-1G>C variant has been reported in multiple ARVC probands (see literature), and has been found to segregate with disease in a few families … (more)
The PKP2 c.2146-1G>C variant has been reported in multiple ARVC probands (see literature), and has been found to segregate with disease in a few families (Dalal D et al., 2006; Groeneweg JA, et al., 2014; Svensson et al., 2016). The variant affects a canonical splice acceptor site of intron 10 and was found to result in exon 11 skipping and consequently a shift in the reading frame (Groeneweg JA, et al., 2014). The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.00005; http://exac.broadinstitute.org/). We identified this variant in 3 male ARVC probands. 2/3 probands have no family history of disease. The other proband has family history of ARVC and sudden death, and passed away from a cardiac arrest at young age. In summary, based on LOF variants in PKP2 being an established mechanism of ARVC, multiple ARVC probands reported with the variant, cosegregation with disease and rarity in the general population, we classify PKP2 c.2146-1G>C as a "pathogenic" variant. (less)
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Pathogenic
(Nov 08, 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: SCV002579591.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767286.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (ClinVar, PMID: 17010805, PMID: 23183494). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR showed skipping of exon 11, resulting in a frameshift, which is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction) (PMID: 25087486). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other loss of function variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic in multiple families with ARVC (ClinVar, PMID: 27335691). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 05, 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: SCV000893978.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Mar 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333842.3
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
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Pathogenic
(Jan 20, 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
|
Invitae
Accession: SCV000545224.10
First in ClinVar: Oct 22, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 10 of the PKP2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 10 of the PKP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs193922674, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 24784157, 25087486, 27335691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6756). Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 15489853, 25087486). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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PKP2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004740948.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PKP2 c.2146-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is also referred to as … (more)
The PKP2 c.2146-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is also referred to as c.2014-1G>C using an alternate transcript (NM_001005242.3). This variant has been reported to be causative for arrhythmogenic right ventricular dysplasia (ARVD; Gerull et al. 2004. PubMed ID: 15489853; La Gerche et al. 2010. PubMed ID: 20525856; Perrin et al. 2013. PubMed ID: 23810883; OMIM #609040). In ClinVar, this variant is interpreted as pathogenic by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6756/). Furthermore, protein truncating variants up and downstream of this variant have been reported to be causative for ARVD (Gerull et al. 2004. PubMed ID: 15489853; Bao et al. 2013. PubMed ID: 24125834; Walsh et al. 2017. PubMed ID: 27532257). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. (less)
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Pathogenic
(May 04, 2015)
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criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207157.3
First in ClinVar: Feb 06, 2015 Last updated: Sep 22, 2018 |
Number of individuals with the variant: 2
|
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Pathogenic
(May 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744696.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
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Pathogenic
(Jun 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840038.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
This c.2146-1G>C variant has been reported in over 10 individuals with ARVD/cardiomyopathy with incomplete family segregation [PMID 15489853,17010805, 20525856, 24784157, 25087486]. This variant is located … (more)
This c.2146-1G>C variant has been reported in over 10 individuals with ARVD/cardiomyopathy with incomplete family segregation [PMID 15489853,17010805, 20525856, 24784157, 25087486]. This variant is located in the invariant splice acceptor site of intron 11. Functional assays showed that this change activates a cryptic splice acceptor site in intron 12 or, alternatively, another cryptic splice acceptor site in PKP2 exon 13 [PMID 15489853]. A variant affecting the same invariant splice site has also been reported in additional patients [PMID 19955750]. This variant has been detected in 6 heterozygous individuals from Europe (http://exac.broadinstitute.org/variant/12-32955491-C-G). It is thus classified as a pathogenic variant. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987537.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
|
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Pathogenic
(May 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001190256.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Secondary finding: yes
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: no
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440289.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760302.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
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Pathogenic
(May 01, 2021)
|
criteria provided, single submitter
Method: research
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
unknown
|
Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538614.1
First in ClinVar: Jul 01, 2022 Last updated: Jul 01, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
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Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000319827.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.2146-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 11 of the PKP2 gene. This mutation … (more)
The c.2146-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 11 of the PKP2 gene. This mutation has been observed in numerous unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was shown to segregate with disease in multiple families, though penetrance and expressivity were variable (Gerull B et al. Nat. Genet. 2004;36(11):1162-4; Dalal D et al. J. Am. Coll. Cardiol. 2006;48(7):1416-24, Svensson A et al Am. J. Cardiovasc. Dis. 2016;6(2):55-65). Functional studies on mRNA demonstrated that this mutation results in exon 11 skipping (Groeneweg JA et al. Heart Rhythm 2014;11(11):2010-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
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Pathogenic
(Dec 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
|
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV002764829.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Seizure (present) , Secondary microcephaly (present) , Encephalopathy (present) , Global developmental delay (present)
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Pathogenic
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000236252.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple individuals with ARVC referred for testing at GeneDx and in published literature (Gerull et al., 2004; Syrris et al., 2006; Dalal et … (more)
Reported in multiple individuals with ARVC referred for testing at GeneDx and in published literature (Gerull et al., 2004; Syrris et al., 2006; Dalal et al., 2006; den Haan et al., 2009; Watkins et al., 2009; Fressart et al., 2010; Tan et al., 2010; Perrin et al., 2013; Kant et al., 2016; Svensson et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional studies revealed c.2146-1 G>C causes skipping of exon 11, resulting in a shift in reading frame (Groeneweg et al., 2014); This variant is associated with the following publications: (PMID: 20525856, 20152563, 16415378, 19279339, 30790397, 30868567, 21606390, 20864495, 25525159, 19880068, 20857253, 15489853, 17010805, 18554203, 20031617, 20400443, 27335691, 26676851, 24784157, 23810883, 28518168, 28253841, 29997227, 27532257, 24585727, 23812740, 21636032, 21606396, 28177452, 26264440, 25351510, 19863551, 19302745, 29253866, 30998997, 30677492, 19955750, 16549640, 31737537, 31447099, 25825460, 32372669, 31386562, 31402444, 25087486, 32522011, 33232181, 33238575, 32686758, 34135346, 33087929) (less)
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Pathogenic
(Sep 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099191.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PVS1, PS4
Secondary finding: yes
|
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Pathogenic
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904636.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to C nucleotide substitution at the -1 position of intron 10 splice acceptor site of the PKP2 gene. Functional RNA … (more)
This variant causes a G to C nucleotide substitution at the -1 position of intron 10 splice acceptor site of the PKP2 gene. Functional RNA studies have shown that this variant causes skipping of exon 11 and a premature truncation of the PKP2 gene product (PMID: 15489853, 25087486). This variant has been reported in over 40 individuals affected with arrhythmogenic cardiomyopathy (PMID: 15489853, 17010805, 17010805, 20031617, 20400443, 20857253, 23178689, 24784157, 25087486, 25087486, 27335691, 28523642, 35579515) and has been shown to segregate with disease in multiple families (PMID: 25087486, 27335691). This variant has been identified in 9/282670 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 available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250082.18
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Comment:
PKP2: PVS1, PS4:Moderate
Number of individuals with the variant: 6
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Likely pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Arrhythmogenic right ventricular dysplasia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190460.1 First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015 |
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Pathogenic
(Jun 20, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280410.1
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS10-1 G>C (c.2146-1 G>C) in intron 10 of the PKP2 gene (NM_004572.3) Given the strong case data and the fact that many splicing variants in PKP2 have been implicated in ARVC, we consider this variant very likely disease causing. The variant has been seen in at least 37 unrelated cases of ARVC (not including this patient's family). There is weak segregation data. Gerull et al (2004) observed the variant in two of 120 unrelated patients with ARVC of European decent who underwent sequencing of PKP2. Syrris et al (2006) observed the variant in one of 100 white patients from their British ARVC cohort (McKenna's group). Dalal et al (2006) observed the variant in 7 of 58 patients with ARVC in the Hopkins ARVC registry (note that 15 patients in the cohort were also enrolled in the national ARVC registry so may overlap with other reports). The same group reported in a separate paper on two of these families; in one family two affected invidiuals had the variant while in the other family two identical twins both had the variant. This group later reported on analysis of PKP2, DSG2, DSP, DSC2, and JUP in 82 patients with ARVC from the Hopkins registry; 10 patients have this variant, which appears to include the 7 previously reported (den Haan et al 2009). One of these patients had two additional desmosomal variant including a PKP2 missense previously reported with ARVC and a DSG2 missense that has been seen more frequently in both left and right sided cardiomyopathy than in controls and is hypothesized to be a modifier. The Hopkins cases appear to be included in several subsequent publications by their group (Tan et al 2010, Xu et al 2010). Wlodarska et al (2008) in an ESC abstract reported that they observed the variant in one of 42 patients with ARVC who underwent PKP2 screening by DHLPC and sequencing. Ancestry is not noted. Authors are from Italy and Poland. Watkins et al (2009) reported the variant in 1 of 50 unrelated ARVC paitents from their South African registry. Ancestry is not noted. Asimaki et al (2009) include an ARVC patient with this variant in their study on immunhistochemistry findings in ARVC. Unfortunately it is not noted how this patient was ascertained. Given this list of co-authors I suspect the case may come from the Hopkins cohort and thus overlaps with their reports (den Haan et al 2009, Dalal et al 2008). La Gerche et al (2010) analysed desmosomal genes in 47 endurance athletes with complex ventricular arrhythmias with right ventricular morphology. They observed this variant in two of those cases. Unfortunately individual phenotypic data is not provided. Two-thirds of athletes with a pathogenic variant met task force criteria for an ARVC diagnosis. Fressart et al (2010) sequenced five desmosomal genes in 135 patients with ARVC from their French and Swiss cohort and observed the variant in 7 unrelated patients. Borahona-Dussaul et al (2010) observed the variant in one of 23 patients with ARVC from their cohort in Montreal. Cox et al (2011) analyzed five desmosomal genes in their Dutch cohort of 149 ARVC patients and observed this variant in 7 patients. Baskin et al (2013) reported on sequencing of ARVC genes in 195 patients with suspected ARVC either seen in their clinic in Toronto or referred for genetic testing at their Toronto laboratory. Five patients had this variant. Perrin et al (2013) include a patient with this variant in their study on exercise testing in asymptomatic carriers; given the author list this patient was likely drawn from one of the previously published families. Nested RT-PCR on an ARVC patient with this variant showed an aberrant splicing product consistent with altered splicing (Gerull et al 2004). At least two dozen splice variants in this gene have been reported in association with ARVC (see http://www.arvcdatabase.info/). The majority of the disease-associated variants in PKP2 are splicing variants, frameshift, nonsense, or in-frame deletions. In one study 66 of 149 unrelated ARVC patients had such a variant (Cox et al 2011). In contrast, these variants are rare in the general population (Kapplinger et al 2011, NHLBI ESP). In total the variant has been seen in 2 of 7994 published controls and individuals from publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of June 16th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other hypertrophic cardiomyopathy variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Note that a similar analysis is not available for ARVC genes. The variant is listed in dbSNP (rs193922674), with a submission from the above noted ESP data and Correlagen. Presumably the Correlagen data is from a variant found on clinical genetic testing. The variant was not observed in the following published control samples: 250 control individuals (Gerull et al 2004), 200 White control individuals (Syrris et al 2006), 200 control individuals (Dalal et al 2006, den Haan et al 2009), 100 control individuals (Wlodarska et al 2008), 241 controls (86 black African, 80 white, and 75 mixed ancestry; Watkins et al 2009), 300 Caucasians controls (Fressart et al 2010), 200 Caucasians (Cox et al 2011). (less)
Number of individuals with the variant: 38
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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: SCV000733159.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Nov 01, 2004)
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no assertion criteria provided
Method: literature only
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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027344.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2020 |
Comment on evidence:
In 2 unrelated men of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2146-1G-C acceptor splice … (more)
In 2 unrelated men of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2146-1G-C acceptor splice site mutation at the beginning of exon 11. One man had a positive family history; the other had involvement of both ventricles. (less)
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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: SCV001953118.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 21, 2021 |
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Pathogenic
(Nov 24, 2023)
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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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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004171687.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(May 01, 2016)
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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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Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen
Accession: SCV000298150.1
First in ClinVar: Jun 24, 2017 Last updated: Jun 24, 2017 |
Number of individuals with the variant: 2
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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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Arrhythmogenic Right Ventricular Cardiomyopathy Prevalence and Arrhythmic Outcomes in At-Risk Family Members: A Systematic Review and Meta-Analysis. | Sharma A | Circulation. Genomic and precision medicine | 2022 | PMID: 35579515 |
Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
Cardiac sympathectomy for refractory ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy. | Assis FR | Heart rhythm | 2019 | PMID: 30677492 |
Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance. | Haggerty CM | Circulation. Genomic and precision medicine | 2018 | PMID: 29997227 |
Sudden unexplained death in the young: epidemiology, aetiology and value of the clinically guided genetic screening. | Anastasakis A | 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 | 2018 | PMID: 28177452 |
Autosomal Recessive Nonsyndromic Arrhythmogenic Right Ventricular Cardiomyopathy without Cutaneous Involvements: A Novel Mutation. | Soveizi M | Annals of human genetics | 2017 | PMID: 28523642 |
Using high-resolution variant frequencies to empower clinical genome interpretation. | Whiffin N | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28518168 |
Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy. | Bainbridge MN | BMC medical genetics | 2017 | PMID: 28253841 |
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 |
Arrhythmogenic Right Ventricular Cardiomyopathy - 4 Swedish families with an associated PKP2 c.2146-1G>C variant. | Svensson A | American journal of cardiovascular disease | 2016 | PMID: 27335691 |
Loss of plakoglobin immunoreactivity in intercalated discs in arrhythmogenic right ventricular cardiomyopathy: protein mislocalization versus epitope masking. | Kant S | Cardiovascular research | 2016 | PMID: 26676851 |
Plakophilin-2 c.419C>T and risk of heart failure and arrhythmias in the general population. | Christensen AH | European journal of human genetics : EJHG | 2016 | PMID: 26264440 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
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 |
Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Groeneweg JA | Heart rhythm | 2014 | PMID: 25087486 |
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. | Lawrence L | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24784157 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. | Philips B | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24585727 |
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. | Baskin B | Human genetics | 2013 | PMID: 23812740 |
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 |
Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. | Noorman M | Heart rhythm | 2013 | PMID: 23178689 |
New insight into the variable expression of arrhythmogenic right ventricular cardiomyopathy provided by the analysis of a plakophilin-2 splice mutation. | Gandjbakhch E | Cardiology | 2012 | PMID: 23183494 |
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 |
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. | Quarta G | Circulation | 2011 | PMID: 21606390 |
Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. | Christensen AH | Journal of medical genetics | 2010 | PMID: 20864495 |
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Tan BY | Journal of cardiovascular translational research | 2010 | PMID: 20857253 |
Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin. | La Gerche A | Heart (British Cardiac Society) | 2010 | PMID: 20525856 |
Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. | Fressart V | 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 | 2010 | PMID: 20400443 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders? | Christensen AH | Cardiology | 2010 | PMID: 19955750 |
Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Barahona-Dussault C | Clinical genetics | 2010 | PMID: 19863551 |
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | den Haan AD | Circulation. Cardiovascular genetics | 2009 | PMID: 20031617 |
Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa. | Watkins DA | Heart rhythm | 2009 | PMID: 19880068 |
Morphologic variants of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy a genetics-magnetic resonance imaging correlation study. | Dalal D | Journal of the American College of Cardiology | 2009 | PMID: 19358943 |
Mutation of plakophilin-2 gene in arrhythmogenic right ventricular cardiomyopathy. | Wu SL | Chinese medical journal | 2009 | PMID: 19302745 |
A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. | Asimaki A | The New England journal of medicine | 2009 | PMID: 19279339 |
Gap junction remodeling in a case of arrhythmogenic right ventricular dysplasia due to plakophilin-2 mutation. | Tandri H | Journal of cardiovascular electrophysiology | 2008 | PMID: 18554203 |
Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Dalal D | Journal of the American College of Cardiology | 2006 | PMID: 17010805 |
Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. | Dalal D | Circulation | 2006 | PMID: 16549640 |
Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. | Syrris P | Circulation | 2006 | PMID: 16415378 |
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 rs193922674 ...
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.