ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.2377del (p.Ser793fs)
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.2377del (p.Ser793fs)
Variation ID: 177995 Accession: VCV000177995.27
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32792712 (GRCh38) [ NCBI UCSC ] 12: 32945646 (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 Dec 19, 2017 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.2377del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Ser793fs frameshift NM_004572.3:c.2509delA NM_004572.4:c.2509del NP_004563.2:p.Ser837fs frameshift NC_000012.12:g.32792713del NC_000012.11:g.32945647del NG_009000.1:g.109135del LRG_398:g.109135del - Protein change
- S793fs
- Other names
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- Canonical SPDI
- NC_000012.12:32792711:TT:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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 |
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 21, 2017 | RCV000154671.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV000183778.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2019 | RCV000251945.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000470468.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2018 | RCV000852448.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2022 | RCV001191916.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 14, 2022 | RCV002469029.1 |
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
(May 07, 2017)
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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: SCV000748003.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Likely pathogenic
(Jul 21, 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
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204349.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
The p.Ser837fs variant in PKP2 has been reported in >10 individuals with clinica l features of ARVC (Gerull 2004, Dalal 2006, Dalal 2006, Dalal 2009, … (more)
The p.Ser837fs variant in PKP2 has been reported in >10 individuals with clinica l features of ARVC (Gerull 2004, Dalal 2006, Dalal 2006, Dalal 2009, Xu 2010, An toniades 2006, Fressart 2009, Barahona-Dussault 2010, Den Haan 2009, Watkins 200 9, Tan, 2010, Cox 2011, Baskin 2013) and was absent from large population studie s. It has also been reported by other clinical laboratories in ClinVar (Variatio n ID 177995). This variant causes a frameshift, which is predicted to replace th e last 45 amino acid residues of the protein with 93 aberrant residues. This alt eration is predicted to lead to an elongated protein with a termination codon th at is 94 amino acids downstream of the frameshift. In summary, although addition al functional studies are required to fully establish its clinical significance, the p.Ser837fs variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS 4_M, PM4 (Richards 2015). (less)
Number of individuals with the variant: 7
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Pathogenic
(Sep 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ventricular tachycardia
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995140.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000320265.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.2509delA pathogenic mutation, located in coding exon 13 of the PKP2 gene, results from a deletion of one nucleotide at position 2509, causing a … (more)
The c.2509delA pathogenic mutation, located in coding exon 13 of the PKP2 gene, results from a deletion of one nucleotide at position 2509, causing a translational frameshift with a predicted alternate stop codon (p.S837Vfs*94). This variant results in a frameshift which replaces the last 45 amino acids with 93 aberrant amino acids at the 3' terminus of PKP2, elongating the protein. This variant has been reported in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat Genet. 2004;36(11):1162-4; Dalal D et al. Circulation. 2006;113(13):1641-9; Dalal D et al. J Am Coll Cardiol. 2006;48(7):1416-24; Watkins DA et al. Heart Rhythm. 2009;6(11 Suppl):S10-7; Fressart V et al. Europace. 2010;12(6):861-8; Cox MG et al. Circulation. 2011;123(23):2690-700; Baskin B et al. Hum Genet. 2013;132(11):1245-52; Philips B et al. Circ Arrhythm Electrophysiol. 2014;7(2):230-6; Hermida A. Eur. J. Heart Fail. 2019;21(6):792-800). This variant was also reported to co-segregate with disease in a few small families with ARVC (Antoniades L et al. Eur Heart J. 2006;27(18):2208-16; Vouliotis A et al. Hosp Chron. 2015;10(3):166-173; Xu T. J. Am. Coll. Cardiol. 2010;55(6):587-97). This variant was also detected in an eight year old proband with hypertrophic cardiomyopathy and her unaffected father (Haggerty CM. Circ Genom Precis Med. 2018 Jul;11(7):e002237). While the exact impact of the inserted amino acids is unclear, internal structural analysis indicates this alteration may disrupt or destroy a known functional domain (Kirchner F et al. Circ Cardiovasc Genet. 2012;5(4):400-11). Futhermore, a downstream alteration resulting in a similar protein elongation (c.2554delG) has also been reported in association with ARVC (Qiu X. Am. J. Cardiol. 2009;103(10):1439-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated arrhythmogenic right ventricular dysplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766271.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: PKP2 c.2509delA (p.Ser837ValfsX94) causes a frameshift which results in an extension of the protein. The variant was absent in 251916 control chromosomes. c.2509delA … (more)
Variant summary: PKP2 c.2509delA (p.Ser837ValfsX94) causes a frameshift which results in an extension of the protein. The variant was absent in 251916 control chromosomes. c.2509delA has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Gerull_2004, Dalal_2006, den Haan_2009, Dalal_2006, Antoniades_2006, Asimaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 18, 2021)
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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: SCV002043318.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000236259.13
First in ClinVar: Jul 05, 2015 Last updated: Aug 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 93 different amino acids, and other frameshift and missense variants within the residues lost have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 23812740, 15489853, 19863551, 29997227, 29606362, 17010805, 24585727, 23871674, 21606396, 19880068, 18382419, 19358943, 20857253, 20031617, 16893920, 27532257, 30790397, 30764827, 31447099, 32372669, 31402444, 32522011, 25825460, 31386562, 34120153, 35819174, 36139162, 31319917, 16549640, 20400443, VouliotisA2015[CaseReport], 19279339, 20152563) (less)
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Pathogenic
(Jan 29, 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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Invitae
Accession: SCV000545235.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change results in a frameshift in the PKP2 gene (p.Ser837Valfs*94). While this is not anticipated to result in nonsense mediated decay, it is … (more)
This sequence change results in a frameshift in the PKP2 gene (p.Ser837Valfs*94). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PKP2 protein and extend the protein by 48 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 16893920, 17010805, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177995). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 17, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001359851.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to … (more)
This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. This variant has been reported in over 10 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727) and has been shown to segregate with disease in multiple families (PMID: 16893920, 17010805). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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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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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 |
Non-familial cardiomyopathies in Lebanon: exome sequencing results for five idiopathic cases. | Refaat MM | BMC medical genomics | 2019 | PMID: 30764827 |
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 |
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 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. | Philips B | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24585727 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers. | Groeneweg JA | The American journal of cardiology | 2013 | PMID: 23871674 |
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. | Baskin B | Human genetics | 2013 | PMID: 23812740 |
Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations. | Kirchner F | Circulation. Cardiovascular genetics | 2012 | PMID: 22781308 |
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 |
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Tan BY | Journal of cardiovascular translational research | 2010 | PMID: 20857253 |
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 |
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 |
Mutations of plakophilin-2 in Chinese with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Qiu X | The American journal of cardiology | 2009 | PMID: 19427443 |
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 |
A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. | Asimaki A | The New England journal of medicine | 2009 | PMID: 19279339 |
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 |
Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis. | Antoniades L | European heart journal | 2006 | PMID: 16893920 |
Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. | Dalal D | Circulation | 2006 | PMID: 16549640 |
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 rs727504432 ...
HelpRecord last updated Feb 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.