VCV000202022.15 - ClinVar

NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

Germline

Classification

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.

(6)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

Variation ID: 202022 Accession: VCV000202022.15

Type and length

Deletion, 1 bp

Location

Cytogenetic: 12p11.21 12: 32821488 (GRCh38) [ NCBI UCSC ] 12: 32974422 (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	May 29, 2016	May 1, 2024	Jul 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1881del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Lys628fs	frameshift
NM_004572.3:c.2013delC
NM_004572.4:c.2013del	NP_004563.2:p.Lys672fs	frameshift
NC_000012.12:g.32821491del
NC_000012.11:g.32974425del
NG_009000.1:g.80359del
LRG_398:g.80359del
LRG_398t1:c.2013del	LRG_398p1:p.Lys672fs

... more HGVS ... less HGVS

Protein change

K628fs, K672fs

Other names

Canonical SPDI

NC_000012.12:32821487:GGGG:GGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA011637 dbSNP: rs764817683 VarSome

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
Gene	OMIM	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	1943	1996

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2023	RCV000183795.11
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Mar 21, 2019	RCV001183812.11
Arrhythmogenic right ventricular dysplasia 9	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2023	RCV001852371.12
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Aug 31, 2020	RCV002415788.9
Cardiac arrhythmia	Pathogenic (1)	criteria provided, single submitter	Jan 2, 2018	RCV001842942.9
Arrhythmogenic right ventricular cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	May 22, 2023	RCV004017464.2

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 (Jan 02, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Arrhythmia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918022.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (10) PubMed: 17010805‚ 16549640‚ 20031617‚ 23354045‚ 25971409‚ 28097316‚ 29221435‚ 24768880‚ 20857253‚ 21723241 Comment: Variant summary: The PKP2 c.2013delC (p.Lys672ArgfsX12) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense … (more) Variant summary: The PKP2 c.2013delC (p.Lys672ArgfsX12) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2197_2202delinsG, p.His733fsX8; ). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/247018 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). The variant has been reported in numerous affected individuals and families, and has been reported to segregate in families with ARVD, albeit with less than full penetrance (Dalal_2006, Konig_2017, Arbustini_2014). A functional study has shown the variant leads to undetectable mutant cDNA levels indicating instability and degredation (Kim_2013). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Mar 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001349645.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 15, 2022	Comment: This variant deletes 1 nucleotide in exon 10 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotide in exon 10 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23354045, 24967631, 25971409, 26590176). This variant has been identified in 2/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jul 13, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236276.11 First in ClinVar: Jul 05, 2015 Last updated: Jul 22, 2023	Comment: Frameshift 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; Published … (more) Frameshift 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; Published functional studies using patient derived cells demonstrated abnormal nuclear translocation of junction plakoglobin, suggesting mutant PKP2 transcripts are unstable and degraded to undetectable levels (Kim et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26389801, 25344329, 24585727, 23671136, 25815118, 27110425, 24657289, 24576884, 25971409, 24920660, 16549640, 24070718, 24967631, 21723241, 23889974, 19358943, 26590176, 20031617, 23810894, 17010805, 23871885, 20857253, 29221435, 30302938, 30205876, 31533459, 31386562, 31402444, 28097316, 33087929, 35653365, 35536239, 32485643, 23354045) (less)
Pathogenic (Jun 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002119543.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 15489853‚ 23911551‚ 16549640‚ 17010805‚ 24070718‚ 24585727‚ 29221435 Comment: This variant is present in population databases (rs764817683, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 202022). For these reasons, this variant … (more) This variant is present in population databases (rs764817683, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 202022). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys672Argfs*12) 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 also known as 2011delC (p.671fsX683) and c.2009delC (p.K672RfsX12). This premature translational stop signal has been observed in individuals with Arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 17010805, 24070718, 24585727, 29221435). It has also been observed to segregate with disease in related individuals. (less)
Pathogenic (May 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848345.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (20) PubMed: 17010805‚ 20031617‚ 23354045‚ 28097316‚ 16549640‚ 21723241‚ 24768880‚ 29221435‚ 20857253‚ 24585727‚ 15489853‚ 25971409‚ 31386562‚ 31402444‚ 24576884‚ 23911551‚ 24967631‚ 24070718‚ 33087929‚ 34550725 Comment: The p.Lys672ArgfsX12 variant in PKP2 has been reported in at least 6 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 7 … (more) The p.Lys672ArgfsX12 variant in PKP2 has been reported in at least 6 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 7 affected relatives from 3 families (Tan 2010 PMID: 20857253, Philips 2014 PMID: 24585727, Kim 2013 PMID: 23354045, den Haan 2009 PMID: 20031617, Dalal 2006 PMID: 17010805 Dalal 2006 PMID: 16549640, Bauce 2011 PMID: 21723241, Arbustini 2014 PMID: 24768880, Alcalde 2014 PMID: 24967631, Mast 2017 PMID: 28097316, Konig 2017 PMID: 29221435, van Lint 2019 PMID: 31386562). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 202022) and has been identified in 0.0018% (1/68034) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 672 and leads to a premature termination codon 12 amino acids downstream. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4_moderate, PP1_Strong, PM2_Supporting. (less)
Pathogenic (Aug 31, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002720307.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 16549640‚ 20031617‚ 24070718‚ 29221435 Comment: The c.2013delC pathogenic mutation, located in coding exon 10 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 2013, causing … (more) The c.2013delC pathogenic mutation, located in coding exon 10 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 2013, causing a translational frameshift with a predicted alternate stop codon (p.K672Rfs*12). This alteration has been reported in individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Dalal D et al. Circulation, 2006 Apr;113:1641-9; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42; König E et al. BMC Med. Genet., 2017 12;18:145). 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)

Comment:

Variant summary: The PKP2 c.2013delC (p.Lys672ArgfsX12) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2197_2202delinsG, p.His733fsX8; ). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/247018 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). The variant has been reported in numerous affected individuals and families, and has been reported to segregate in families with ARVD, albeit with less than full penetrance (Dalal_2006, Konig_2017, Arbustini_2014). A functional study has shown the variant leads to undetectable mutant cDNA levels indicating instability and degredation (Kim_2013). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 10 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23354045, 24967631, 25971409, 26590176). This variant has been identified in 2/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

Comment:

Frameshift 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; Published functional studies using patient derived cells demonstrated abnormal nuclear translocation of junction plakoglobin, suggesting mutant PKP2 transcripts are unstable and degraded to undetectable levels (Kim et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26389801, 25344329, 24585727, 23671136, 25815118, 27110425, 24657289, 24576884, 25971409, 24920660, 16549640, 24070718, 24967631, 21723241, 23889974, 19358943, 26590176, 20031617, 23810894, 17010805, 23871885, 20857253, 29221435, 30302938, 30205876, 31533459, 31386562, 31402444, 28097316, 33087929, 35653365, 35536239, 32485643, 23354045)

Comment:

This variant is present in population databases (rs764817683, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 202022). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys672Argfs*12) 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 also known as 2011delC (p.671fsX683) and c.2009delC (p.K672RfsX12). This premature translational stop signal has been observed in individuals with Arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 17010805, 24070718, 24585727, 29221435). It has also been observed to segregate with disease in related individuals.

Comment:

The p.Lys672ArgfsX12 variant in PKP2 has been reported in at least 6 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 7 affected relatives from 3 families (Tan 2010 PMID: 20857253, Philips 2014 PMID: 24585727, Kim 2013 PMID: 23354045, den Haan 2009 PMID: 20031617, Dalal 2006 PMID: 17010805 Dalal 2006 PMID: 16549640, Bauce 2011 PMID: 21723241, Arbustini 2014 PMID: 24768880, Alcalde 2014 PMID: 24967631, Mast 2017 PMID: 28097316, Konig 2017 PMID: 29221435, van Lint 2019 PMID: 31386562). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 202022) and has been identified in 0.0018% (1/68034) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 672 and leads to a premature termination codon 12 amino acids downstream. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4_moderate, PP1_Strong, PM2_Supporting.

Comment:

The c.2013delC pathogenic mutation, located in coding exon 10 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 2013, causing a translational frameshift with a predicted alternate stop codon (p.K672Rfs*12). This alteration has been reported in individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Dalal D et al. Circulation, 2006 Apr;113:1641-9; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42; König E et al. BMC Med. Genet., 2017 12;18:145). 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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epicardial differentiation drives fibro-fatty remodeling in arrhythmogenic cardiomyopathy.	Kohela A	Science translational medicine	2021	PMID: 34550725
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data.	Ye JZ	Clinical genetics	2019	PMID: 31402444
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.	van Lint FHM	Circulation. Genomic and precision medicine	2019	PMID: 31386562
Exploring digenic inheritance in arrhythmogenic cardiomyopathy.	König E	BMC medical genetics	2017	PMID: 29221435
Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.	Mast TP	JAMA cardiology	2017	PMID: 28097316
Maturation-Based Model of Arrhythmogenic Right Ventricular Dysplasia Using Patient-Specific Induced Pluripotent Stem Cells.	Wen JY	Circulation journal : official journal of the Japanese Circulation Society	2015	PMID: 25971409
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
Reply: The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: more questions than answers?	Arbustini E	Journal of the American College of Cardiology	2014	PMID: 24768880
Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear.	Philips B	Circulation. Arrhythmia and electrophysiology	2014	PMID: 24585727
Human-induced pluripotent stem cell models of inherited cardiomyopathies.	Karakikes I	Current opinion in cardiology	2014	PMID: 24576884
Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.	Rigato I	Circulation. Cardiovascular genetics	2013	PMID: 24070718
Mechanistic basis of desmosome-targeted diseases.	Al-Jassar C	Journal of molecular biology	2013	PMID: 23911551
Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs.	Kim C	Nature	2013	PMID: 23354045
Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations.	Bauce B	Heart rhythm	2011	PMID: 21723241
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy.	Tan BY	Journal of cardiovascular translational research	2010	PMID: 20857253
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy.	den Haan AD	Circulation. Cardiovascular genetics	2009	PMID: 20031617
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
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 rs764817683 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs764817683 ...