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

gnomAD frequency: 0.00041  dbSNP: rs199601548

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183769	SCV000236250	uncertain significance	not provided	2024-09-23	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232789	SCV000288601	likely benign	Arrhythmogenic right ventricular dysplasia 9	2023-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000232789	SCV000743464	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-07-19	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000232789	SCV000744717	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-05-31	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000232789	SCV000803625	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2018-05-31	criteria provided, single submitter	curation	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).
CeGaT Center for Human Genetics Tuebingen	RCV000183769	SCV001148703	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000232789	SCV001266945	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2019-09-17	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170221	SCV001332781	uncertain significance	Cardiomyopathy	2018-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170221	SCV001356370	likely benign	Cardiomyopathy	2019-11-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844049	SCV002103758	uncertain significance	not specified	2024-02-27	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002408659	SCV002717109	uncertain significance	Cardiovascular phenotype	2024-02-01	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000232789	SCV003800435	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-04-21	criteria provided, single submitter	clinical testing	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000232789	SCV003920328	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-03-30	criteria provided, single submitter	clinical testing	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.
Dept of Medical Biology, Uskudar University	RCV003318353	SCV004022035	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BP1
Mayo Clinic Laboratories, Mayo Clinic	RCV000183769	SCV005408301	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	PS3_supporting
CSER _CC_NCGL, University of Washington	RCV000148732	SCV000190467	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000232789	SCV000733172	uncertain significance	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183769	SCV001925007	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183769	SCV001959480	uncertain significance	not provided		no assertion criteria provided	clinical testing