ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.2071C>T (p.Arg691Ter)
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
-
NM_001005242.3(PKP2):c.2071C>T (p.Arg691Ter)
Variation ID: 6755 Accession: VCV000006755.30
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p11.21 12: 32802499 (GRCh38) [ NCBI UCSC ] 12: 32955433 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 20, 2024 Dec 9, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001005242.3:c.2071C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Arg691Ter nonsense NM_004572.4:c.2203C>T NP_004563.2:p.Arg735Ter nonsense NC_000012.12:g.32802499G>A NC_000012.11:g.32955433G>A NG_009000.1:g.99348C>T LRG_398:g.99348C>T LRG_398t1:c.2203C>T LRG_398p1:p.Arg735Ter - Protein change
- R735*, R691*
- Other names
- -
- Canonical SPDI
- NC_000012.12:32802498:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
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. |
|||
PKP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1895 | 1948 |
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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, single submitter
|
Nov 17, 2023 | RCV000007147.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 9, 2023 | RCV000211738.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2022 | RCV001557815.15 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 4, 2022 | RCV002426495.2 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Apr 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002727510.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R735* pathogenic mutation (also known as c.2203C>T), located in coding exon 11 of the PKP2 gene, results from a C to T substitution at … (more)
The p.R735* pathogenic mutation (also known as c.2203C>T), located in coding exon 11 of the PKP2 gene, results from a C to T substitution at nucleotide position 2203. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat. Genet., 2004 Nov;36:1162-4; Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Alcalde M et al. PLoS ONE, 2014 Jun;9:e100560; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). Transgenic mice with cardiac-specific expression of this variant developed exercise-dependent right ventricular dysfunction resembling ARVC (Cruz FM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1438-50). 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)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839393.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.2203C>T (p.Arg735*) variant in exon 11 of PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead … (more)
The c.2203C>T (p.Arg735*) variant in exon 11 of PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been reported in several unrelated individuals (>15) with arrhythmogenic cardiomyopathy (PMID:32389048, 32268277, 30385303, 28471438, 31319917, 29178656, 24125834, 15489853), also found to be segregated in a family with four affected individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID:24967631). Functional studies on transgenic mice showed that cardiac overexpression of human p.Arg735* in mice induced exercise dependent ARVC phenotype, and thus the pathogenic mechanism of this variant was concluded as dominant negative (PMID: 25857910). This variant was found to be rare (1/251356; 0.000003978) in the general population database gnomAD and classified as pathogenic by several ClinVar submitters (ClinVar ID: 6755). 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/D (PMID: 26743238, 15489853, 17010805, 20031616, 20031617) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 640578, 202005, 6757). Therefore, the c.2203C>T (p.Arg735*) variant in the PKP2 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 26, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205873.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
The p.Arg735X variant in PKP2 has been reported in 7 individuals with clinical f eatures of ARVC and segregated with disease in 3 affected relatives … (more)
The p.Arg735X variant in PKP2 has been reported in 7 individuals with clinical f eatures of ARVC and segregated with disease in 3 affected relatives (Gerull 2004 , Bao 2013, Alcalde 2014, LMM data). This variant has been identified in 1/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs121434421) and has been reported in ClinVar (Vari ation ID 6755). This nonsense variant leads to a premature termination codon at position 735, which is predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. Transgenic mice expressing p.Arg735X mutant protein in cardiac tissue res ulted in exercise-dependent ARVC phenotype (Cruz 2015). In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner based. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1; PS3_Supp orting. (less)
Number of individuals with the variant: 2
|
|
Pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001779650.4
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
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 disease; Functional … (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; Functional studies show that over-expression of human p.(R735*) in mice induced an exercise-dependent ARVC phenotype (Cruz et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32466575, 24125834, 25525159, 17363426, 18382419, 24832006, 24967631, 28008009, 30385303, 28471438, 29178656, 29606362, 30790397, 31737537, 32268277, 32372669, 31386562, 31402444, 33232181, 15489853, 25857910) (less)
|
|
Pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000545246.5
First in ClinVar: May 29, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg735*) 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.Arg735*) 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 present in population databases (rs121434421, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with arrythmogenic ventricular cardiomyopathy (ARVC) (PMID: 15489853, 24125834, 24967631). ClinVar contains an entry for this variant (Variation ID: 6755). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002545017.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
PKP2: PVS1, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 2
|
|
Pathogenic
(Nov 01, 2004)
|
no assertion criteria provided
Method: literature only
|
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027343.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 03, 2020 |
Comment on evidence:
In a man and woman of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2203C-T transition … (more)
In a man and woman of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2203C-T transition in exon 11 of the PKP2 gene resulting in an arg735-to-stop (R735X) substitution. The woman had a positive family history and involvement of both the right and the left ventricles. (less)
|
|
Pathogenic
(Jun 26, 2019)
|
no assertion criteria provided
Method: research
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430828.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this … (more)
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. (less)
|
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 |
---|---|---|---|---|
The genetic architecture of Plakophilin 2 cardiomyopathy. | Dries AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34120153 |
Clinical and Genetic Findings in Children Presenting With Ventricular Fibrillation as the First Manifestation of Cardiovascular Disease. | Hylind RJ | Journal of the American Heart Association | 2020 | PMID: 32389048 |
Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. | Campuzano O | EBioMedicine | 2020 | PMID: 32268277 |
Phenotypic Manifestations of Arrhythmogenic Cardiomyopathy in Children and Adolescents. | DeWitt ES | Journal of the American College of Cardiology | 2019 | PMID: 31319917 |
Sarcomere variants in arrhythmogenic cardiomyopathy: Pathogenic factor or bystander? | Chen K | Gene | 2019 | PMID: 30385303 |
Usefulness of Genetic Study by Next-generation Sequencing in High-risk Arrhythmogenic Cardiomyopathy. | Ruiz Salas A | Revista espanola de cardiologia (English ed.) | 2018 | PMID: 29606362 |
Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Wada Y | Molecular genetics & genomic medicine | 2017 | PMID: 29178656 |
Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients. | Pilichou K | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 29038103 |
Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
Exercise triggers ARVC phenotype in mice expressing a disease-causing mutated version of human plakophilin-2. | Cruz FM | Journal of the American College of Cardiology | 2015 | PMID: 25857910 |
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 |
Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy. | Bao J | Circulation. Cardiovascular genetics | 2013 | PMID: 24125834 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | den Haan AD | Circulation. Cardiovascular genetics | 2009 | PMID: 20031617 |
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 |
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 |
Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. | Gerull B | Nature genetics | 2004 | PMID: 15489853 |
click to load more click to collapse |
Text-mined citations for rs121434421 ...
HelpRecord last updated Apr 20, 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.