VCV000161332.61 - ClinVar

NM_001005242.3(PKP2):c.184C>A (p.Gln62Lys)

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.

(19)

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.

Conflicting classifications of pathogenicity
Uncertain significance(13); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001005242.3(PKP2):c.184C>A (p.Gln62Lys)

Variation ID: 161332 Accession: VCV000161332.61

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 33049482 (GRCh37) [ NCBI UCSC ] 12: 32896548 (GRCh38) [ 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	Dec 7, 2014	Nov 24, 2024	Sep 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.184C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Gln62Lys	missense
NM_004572.4:c.184C>A	NP_004563.2:p.Gln62Lys	missense
NC_000012.12:g.32896548G>T
NC_000012.11:g.33049482G>T
NG_009000.1:g.5299C>A
LRG_398:g.5299C>A
LRG_398t1:c.184C>A	LRG_398p1:p.Gln62Lys
	Q99959:p.Gln62Lys

... more HGVS ... less HGVS

Protein change

Q62K

Other names

p.Q62K:CAG>AAG
NM_001005242.2(PKP2):c.184C>A(p.Gln62Lys)
NM_004572.3(PKP2):c.184C>A(p.Gln62Lys)

Canonical SPDI

NC_000012.12:32896547:G:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00014

Exome Aggregation Consortium (ExAC) 0.00017

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00024

The Genome Aggregation Database (gnomAD) 0.00041

Trans-Omics for Precision Medicine (TOPMed) 0.00046

Links

ClinGen: CA010651 UniProtKB: Q99959#VAR_065703 dbSNP: rs199601548 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.
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Jun 1, 2014	RCV000148732.4
not provided	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Sep 23, 2024	RCV000183769.35
Arrhythmogenic right ventricular dysplasia 9	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	Dec 20, 2023	RCV000232789.25
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 8, 2024	RCV003318353.3
Cardiomyopathy	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 12, 2019	RCV001170221.7
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 27, 2024	RCV001844049.3
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 1, 2024	RCV002408659.4

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.
Uncertain significance (Sep 17, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001266945.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (8) PubMed: 25676813‚ 16567567‚ 19569224‚ 17521752‚ 19955750‚ 24352520‚ 20129281‚ 21397041 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 18, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001332781.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Uncertain significance (Jan 08, 2024)	criteria provided, single submitter (Dept of Medical Biology Variant Classification) Method: research	Long QT syndrome Affected status: yes Allele origin: unknown	Dept of Medical Biology, Uskudar University Accession: SCV004022035.2 First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024	Comment: Criteria: BP1 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Turkish Geographic origin: Turkey
Uncertain significance (Jul 19, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) 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: SCV000743464.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Uncertain significance (May 31, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) 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: SCV000744717.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Uncertain significance (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Arrhythmogenic right ventricular dysplasia 9 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803625.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (1) PubMed: 19533476 Comment: This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 9, in Autosomal Dominant manner. The following ACMG Tag(s) … (more) This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 9, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting . PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:19533476). (less)
Likely benign (Nov 12, 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: SCV001356370.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Apr 21, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003800435.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: The PKP2 c.184C>A; p.Gln62Lys variant (rs199601548) variant has been published in multiple unrelated individuals affected with arrhythmogenic right ventricular dysplasia or cardiomyopathy (Bauce 2010, Cerrone … (more) The PKP2 c.184C>A; p.Gln62Lys variant (rs199601548) variant has been published in multiple unrelated individuals affected with arrhythmogenic right ventricular dysplasia or cardiomyopathy (Bauce 2010, Cerrone 2014, Christensen 2009, Garcia-Pavia 2011, Lahtinen 2011, Sanchez 2016). However, segregation studies demonstrate this variant has been detected in unaffected individuals and failed to segregate with ARVC in at least one family (Bauce 2010, Christensen 2010). Additionally, this variant was detected on the opposite chromosome from a loss of function PKP2 variant in an affected family (Bauce 2010). The variant is reported in the ClinVar database (Variation ID: 161332) and is found in the non-Finnish European population with an allele frequency of 0.029% (33/112,560 alleles) in the Genome Aggregation Database. The glutamine at codon 62 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). Functional studies show this variant disrupted interactions with desmoplakin and decreased function (Cerrone 2014, Hall 2009). Due to conflicting information, the clinical significance of the p.Gln62Lys variant is uncertain at this time. References: Bauce B et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010 Jan;7(1):22-9. PMID: 20129281. Cerrone M et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation. 2014 Mar 11;129(10):1092-103. PMID: 24352520. Christensen AH et al. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders? Cardiology. 2010;115(2):148-54. PMID: 19955750. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Hall C et al. Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. Cell Commun Adhes. 2009;16(1-3):15-27. PMID: 19533476. Lahtinen AM et al. Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2011 Aug;8(8):1214-21. PMID: 21397041. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701. (less)
Uncertain significance (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920328.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: PKP2 NM_004572.3 exon 1 p.Gln62Lys (c.184C>A): This variant has been reported in the literature in at least 6 individuals with ARVC, at least two of … (more) PKP2 NM_004572.3 exon 1 p.Gln62Lys (c.184C>A): This variant has been reported in the literature in at least 6 individuals with ARVC, at least two of which also carried additional disease-causing cardiogenetic variants (van Tintelen 2006 PMID:16567567, Lahtinen 2008 PMID:17521752, Fidler 2009 PMID:18662195, Bauce 2010 PMID:20129281, Christensen 2010 PMID:19955750). Segregation of this variant within families is inconclusive; the variant has been shown to segregate with disease is a small number of families but did not segregate with disease in others (Lahtinen 2008 PMID:17521752, Bauce 2010 PMID:20129281. Christensen 2010 PMID:19955750). This variant has also been reported in an individual with DCM, in an individual with Brugada syndrome, and in a sudden death case (Garcia-Pavia 2011 PMID:21859740, Cerrone 2014 PMID:24352520, Christiansen 2016 PMID:27650956). This variant is present in 0.02% (33/112560) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-33049482-G-T) and is present in ClinVar (Variation ID:161332). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro studies have shown subcellular localization of this mutant protein similar to wildtype protein, but functional studies have demonstrated abnormal interaction of the protein with desmoplakin and decreased sodium currents, suggesting that this variant may impact the protein (Fidler 2009 PMID:18662195, Hall 2009 PMID:19533476, Cerrone 2014 PMID:24352520). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Likely benign (Dec 20, 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: SCV000288601.9 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Uncertain significance (Feb 27, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002103758.2 First in ClinVar: Mar 12, 2022 Last updated: Apr 15, 2024	Publications: PubMed (8) PubMed: 19955750‚ 20129281‚ 21397041‚ 21859740‚ 27930701‚ 24352520‚ 19533476‚ 36178741 Comment: Variant summary: PKP2 c.184C>A (p.Gln62Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: PKP2 c.184C>A (p.Gln62Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 212730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00014 vs 0.00065), allowing no conclusion about variant significance. c.184C>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Lahtinen_2008, Christensen_2009, Bauce_2010), Brugada Syndrome (Cerrone_2014), DCM (Garcia-Pavia_2011, van der Meulen_2022) and HCM (Sanchez_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. However, this variant does not co-segregate with disease in at least one family (Christensen_2009). Co-occurrence with a pathogenic variant has been reported (PKP2 c.2119C>T, Q707X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant disrupted interactions with desmoplakin and decreased sodium current (Hall_2009, Cerrone_2014). The following publications have been ascertained in the context of this evaluation (PMID: 19955750, 20129281, 21397041, 21859740, 27930701, 24352520, 19533476, 36178741). ClinVar contains an entry for this variant (Variation ID: 161332). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717109.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (16) PubMed: 16567567‚ 17521752‚ 18662195‚ 19533476‚ 19955750‚ 20129281‚ 21397041‚ 21859740‚ 23299917‚ 24352520‚ 24618965‚ 25637381‚ 26138720‚ 27650965‚ 28166282‚ 36178741 Comment: The p.Q62K variant (also known as c.184C>A), located in coding exon 1 of the PKP2 gene, results from a C to A substitution at nucleotide … (more) The p.Q62K variant (also known as c.184C>A), located in coding exon 1 of the PKP2 gene, results from a C to A substitution at nucleotide position 184. The glutamine at codon 62 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a variety of clinical phenotypes including arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomypathy (DCM), Brugada syndrome, sudden unexplained death, and hypertrophic cardiomyopathy (HCM), and is often seen with additional alterations in PKP2 and other cardiac-related genes (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Garcia-Pavia P et al. Heart, 2011 Nov;97:1744-52; Cerrone M et al. Circulation, 2014 Mar;129:1092-103; Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Sanchez O et al. PLoS ONE, 2017 Feb;12:e0171893). This alteration has also been detected in unaffected family members and absent in affected relatives with ARVC (Lahtinen AM et al. Int. J. Cardiol., 2008 May;126:92-100; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Christensen AH et al. Cardiology, 2010 Dec;115:148-54). In addition, this variant has been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Dewey FE et al. JAMA, 2014 Mar;311:1035-45). In functional studies, observed results have included decreased connexin43 expression, defects in desmosome assembly, and reduced sodium current (Fidler LM et al. J. Cell. Mol. Med., 2009 Oct;13:4219-28; Hall C et al. Cell Commun. Adhes., 2009;16:15-27; Cerrone M et al. Circulation, 2014 Mar;129:1092-103). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Sep 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236250.14 First in ClinVar: Jul 05, 2015 Last updated: Oct 08, 2024	Comment: Has been reported in multiple unrelated individuals with ARVC, DCM, Brugada syndrome, HCM, and/or sudden death both in published literature and in individuals referred for … (more) Has been reported in multiple unrelated individuals with ARVC, DCM, Brugada syndrome, HCM, and/or sudden death both in published literature and in individuals referred for testing at GeneDx; however, many of these individuals harbor additional variants in the PKP2 gene or other cardiac genes (PMID: 16567567, 17521752, 18662195, 20129281, 19955750, 20152563, 24070718, 26138720, 21859740, 24352520, 27930701, 32917565, 36178741); Published segregation studies show this variant has been observed in both affected and unaffected adult relatives (PMID:17521752, 20129281) and has failed to segregate with ARVC in at least one family (PMID: 19955750); Published functional studies demonstrate p.(Q62K) mutant protein disrupts proper desmosome assembly and leads to reduced sodium current (PMID: 19533476, 24352520); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24618965, 29456632, 23299917, 24352520, 20152563, 24070718, 17521752, 21859740, 26138720, 18662195, 26718681, 21397041, 25637381, 23651034, 27930701, 20129281, 27650965, 30765282, 31737537, 31118017, 30847666, 30764827, 34426522, 30483629, 32880476, 32917565, 25395996, 36178741, 16567567, 19955750, 19533476, 32466575, 38540378) (less)
Uncertain significance (Sep 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408301.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (25) PubMed: 16567567‚ 17521752‚ 18662195‚ 19533476‚ 19955750‚ 20129281‚ 20152563‚ 21397041‚ 21859740‚ 23651034‚ 24070718‚ 24352520‚ 25608792‚ 26138720‚ 26718681‚ 27650965‚ 27930701‚ 29456632‚ 30764827‚ 30765282‚ 30847666‚ 31118017‚ 31737537‚ 32880476‚ 36178741 Comment: PS3_supporting Number of individuals with the variant: 1
Uncertain significance (Dec 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001148703.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001959480.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Arrhythmogenic right ventricular dysplasia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190467.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Arrhythmogenic right ventricular dysplasia 9 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733172.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925007.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 9, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting . PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:19533476).

Comment:

The PKP2 c.184C>A; p.Gln62Lys variant (rs199601548) variant has been published in multiple unrelated individuals affected with arrhythmogenic right ventricular dysplasia or cardiomyopathy (Bauce 2010, Cerrone 2014, Christensen 2009, Garcia-Pavia 2011, Lahtinen 2011, Sanchez 2016). However, segregation studies demonstrate this variant has been detected in unaffected individuals and failed to segregate with ARVC in at least one family (Bauce 2010, Christensen 2010). Additionally, this variant was detected on the opposite chromosome from a loss of function PKP2 variant in an affected family (Bauce 2010). The variant is reported in the ClinVar database (Variation ID: 161332) and is found in the non-Finnish European population with an allele frequency of 0.029% (33/112,560 alleles) in the Genome Aggregation Database. The glutamine at codon 62 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). Functional studies show this variant disrupted interactions with desmoplakin and decreased function (Cerrone 2014, Hall 2009). Due to conflicting information, the clinical significance of the p.Gln62Lys variant is uncertain at this time. References: Bauce B et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010 Jan;7(1):22-9. PMID: 20129281. Cerrone M et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation. 2014 Mar 11;129(10):1092-103. PMID: 24352520. Christensen AH et al. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders? Cardiology. 2010;115(2):148-54. PMID: 19955750. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Hall C et al. Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. Cell Commun Adhes. 2009;16(1-3):15-27. PMID: 19533476. Lahtinen AM et al. Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2011 Aug;8(8):1214-21. PMID: 21397041. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701.

Comment:

PKP2 NM_004572.3 exon 1 p.Gln62Lys (c.184C>A): This variant has been reported in the literature in at least 6 individuals with ARVC, at least two of which also carried additional disease-causing cardiogenetic variants (van Tintelen 2006 PMID:16567567, Lahtinen 2008 PMID:17521752, Fidler 2009 PMID:18662195, Bauce 2010 PMID:20129281, Christensen 2010 PMID:19955750). Segregation of this variant within families is inconclusive; the variant has been shown to segregate with disease is a small number of families but did not segregate with disease in others (Lahtinen 2008 PMID:17521752, Bauce 2010 PMID:20129281. Christensen 2010 PMID:19955750). This variant has also been reported in an individual with DCM, in an individual with Brugada syndrome, and in a sudden death case (Garcia-Pavia 2011 PMID:21859740, Cerrone 2014 PMID:24352520, Christiansen 2016 PMID:27650956). This variant is present in 0.02% (33/112560) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-33049482-G-T) and is present in ClinVar (Variation ID:161332). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro studies have shown subcellular localization of this mutant protein similar to wildtype protein, but functional studies have demonstrated abnormal interaction of the protein with desmoplakin and decreased sodium currents, suggesting that this variant may impact the protein (Fidler 2009 PMID:18662195, Hall 2009 PMID:19533476, Cerrone 2014 PMID:24352520). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

Variant summary: PKP2 c.184C>A (p.Gln62Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 212730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00014 vs 0.00065), allowing no conclusion about variant significance. c.184C>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Lahtinen_2008, Christensen_2009, Bauce_2010), Brugada Syndrome (Cerrone_2014), DCM (Garcia-Pavia_2011, van der Meulen_2022) and HCM (Sanchez_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. However, this variant does not co-segregate with disease in at least one family (Christensen_2009). Co-occurrence with a pathogenic variant has been reported (PKP2 c.2119C>T, Q707X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant disrupted interactions with desmoplakin and decreased sodium current (Hall_2009, Cerrone_2014). The following publications have been ascertained in the context of this evaluation (PMID: 19955750, 20129281, 21397041, 21859740, 27930701, 24352520, 19533476, 36178741). ClinVar contains an entry for this variant (Variation ID: 161332). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The p.Q62K variant (also known as c.184C>A), located in coding exon 1 of the PKP2 gene, results from a C to A substitution at nucleotide position 184. The glutamine at codon 62 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a variety of clinical phenotypes including arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomypathy (DCM), Brugada syndrome, sudden unexplained death, and hypertrophic cardiomyopathy (HCM), and is often seen with additional alterations in PKP2 and other cardiac-related genes (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Garcia-Pavia P et al. Heart, 2011 Nov;97:1744-52; Cerrone M et al. Circulation, 2014 Mar;129:1092-103; Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Sanchez O et al. PLoS ONE, 2017 Feb;12:e0171893). This alteration has also been detected in unaffected family members and absent in affected relatives with ARVC (Lahtinen AM et al. Int. J. Cardiol., 2008 May;126:92-100; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Christensen AH et al. Cardiology, 2010 Dec;115:148-54). In addition, this variant has been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Dewey FE et al. JAMA, 2014 Mar;311:1035-45). In functional studies, observed results have included decreased connexin43 expression, defects in desmosome assembly, and reduced sodium current (Fidler LM et al. J. Cell. Mol. Med., 2009 Oct;13:4219-28; Hall C et al. Cell Commun. Adhes., 2009;16:15-27; Cerrone M et al. Circulation, 2014 Mar;129:1092-103). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

Comment:

Has been reported in multiple unrelated individuals with ARVC, DCM, Brugada syndrome, HCM, and/or sudden death both in published literature and in individuals referred for testing at GeneDx; however, many of these individuals harbor additional variants in the PKP2 gene or other cardiac genes (PMID: 16567567, 17521752, 18662195, 20129281, 19955750, 20152563, 24070718, 26138720, 21859740, 24352520, 27930701, 32917565, 36178741); Published segregation studies show this variant has been observed in both affected and unaffected adult relatives (PMID:17521752, 20129281) and has failed to segregate with ARVC in at least one family (PMID: 19955750); Published functional studies demonstrate p.(Q62K) mutant protein disrupts proper desmosome assembly and leads to reduced sodium current (PMID: 19533476, 24352520); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24618965, 29456632, 23299917, 24352520, 20152563, 24070718, 17521752, 21859740, 26138720, 18662195, 26718681, 21397041, 25637381, 23651034, 27930701, 20129281, 27650965, 30765282, 31737537, 31118017, 30847666, 30764827, 34426522, 30483629, 32880476, 32917565, 25395996, 36178741, 16567567, 19955750, 19533476, 32466575, 38540378)

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
Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification.	van der Meulen MH	Circulation. Genomic and precision medicine	2022	PMID: 36178741
Implications of Genetic Testing in Dilated Cardiomyopathy.	Verdonschot JAJ	Circulation. Genomic and precision medicine	2020	PMID: 32880476
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.	Marschall C	Cardiovascular diagnosis and therapy	2019	PMID: 31737537
Sudden Cardiac Death (SCD) - risk stratification and prediction with molecular biomarkers.	Osman J	Journal of biomedical science	2019	PMID: 31118017
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Heart failure in patients with arrhythmogenic right ventricular cardiomyopathy: Genetic characteristics.	Vischer AS	International journal of cardiology	2019	PMID: 30765282
Non-familial cardiomyopathies in Lebanon: exome sequencing results for five idiopathic cases.	Refaat MM	BMC medical genomics	2019	PMID: 30764827
Arrhythmogenic cardiomyopathy: Identification of desmosomal gene variations and desmosomal protein expression in variation carriers.	Wang L	Experimental and therapeutic medicine	2018	PMID: 29456632
Correction: Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation.	Sanchez O	PloS one	2017	PMID: 28166282
Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation.	Sanchez O	PloS one	2016	PMID: 27930701
Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting.	Christiansen SL	European journal of human genetics : EJHG	2016	PMID: 27650965
Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy.	Zorzi 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	2016	PMID: 26138720
A Genetically Vulnerable Myocardium May Predispose to Myocarditis.	Campuzano O	Journal of the American College of Cardiology	2015	PMID: 26718681
The ARVD/C genetic variants database: 2014 update.	Lazzarini E	Human mutation	2015	PMID: 25676813
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Determining the pathogenicity of genetic variants associated with cardiac channelopathies.	Campuzano O	Scientific reports	2015	PMID: 25608792
Clinical interpretation and implications of whole-genome sequencing.	Dewey FE	JAMA	2014	PMID: 24618965
Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype.	Cerrone M	Circulation	2014	PMID: 24352520
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
Prevalence of arrhythmia-associated gene mutations and risk of sudden cardiac death in the Finnish population.	Lahtinen AM	Annals of medicine	2013	PMID: 23651034
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study.	Garcia-Pavia P	Heart (British Cardiac Society)	2011	PMID: 21859740
Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy.	Lahtinen AM	Heart rhythm	2011	PMID: 21397041
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.	Xu T	Journal of the American College of Cardiology	2010	PMID: 20152563
Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.	Bauce B	Heart rhythm	2010	PMID: 20129281
Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?	Christensen AH	Cardiology	2010	PMID: 19955750
A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy.	van der Zwaag PA	Human mutation	2009	PMID: 19569224
Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability.	Hall C	Cell communication & adhesion	2009	PMID: 19533476
Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations.	Fidler LM	Journal of cellular and molecular medicine	2009	PMID: 18662195
Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy.	Lahtinen AM	International journal of cardiology	2008	PMID: 17521752
Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.	van Tintelen JP	Circulation	2006	PMID: 16567567
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Text-mined citations for rs199601548 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001005242.3(PKP2):c.184C>A (p.Gln62Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199601548 ...