rs121434420

chr12-32879021-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001005242.3(PKP2):c.235C>T(p.Arg79Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000139 in 1,577,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 5.82

Genes affected

PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-32879021-G-A is Pathogenic according to our data. Variant chr12-32879021-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32879021-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.235C>T	p.Arg79Ter	stop_gained	2/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.235C>T	p.Arg79Ter	stop_gained	2/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1425290 Hom.: 0 Cov.: 26 AF XY: 0.0000112 AC XY: 8 AN XY: 711384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:8

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 28, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg79*) 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, 17041889, 23911551). This variant is present in population databases (rs121434420, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 19955750, 21301620, 21606396). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6754). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	A heterozygous c.235C>T (p.R79*) pathogenic variant in the PKP2 gene was detected in this individual. This variant has been previously described in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (PMID 19955750, 15489853, 21301620, 21606396). In addition, experimental studies have shown that this variant results in reduced PKP2 protein expression, a loss of localization to sites of cell-cell contact and reduces interaction with connexin 43 protein in vitro (PMID 19084810). Therefore, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 13, 2020	ACMG codes:PVS1, PS4, PS3, PM2, PP1S -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant reduces the expression level of plakophilin and alters desmosomal protein-protein interactions (Joshi-Mukherjee et al., 2008; Rasmussen et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31386562, 23810883, 24704780, 15489853, 16549640, 16567567, 20031617, 19955750, 21301620, 20829228, 22177269, 24125834, 25765472, 26800703, 21606396, 27532257, 20857253, 28152038, 23889974, 23178689, 30847666, 31737537, 31447099, 31402444, 20031616, 19084810, 33662488, 33232181, 32372669, 32522011, 31729605, 33500567) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PKP2: PVS1, PM2, PS4:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 29, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg79Stop (c.235 C>T) in the PKP2 gene. This variant has been reported in at least 20 unrelated individuals with ARVC. The variant was first reported by Gerull et al (2004) in six unrelated individuals with ARVC. Van Tintelen et al (2006) then reported the variant in five unrelated individuals with ARVC. The same group later published 12 unrelated ARVC cases with the variant (including some of their original cases) (van der Zwaag et al 2010). Haplotype analysis supported a founder effect. The authors provide segregation data for 8 families with 2-3 affected individuals with the variant in each family. There were no individuals with definite or probable ARVC who did not have the variant. Christensen et al (2010) reported another patient with ARVC and this variant. Klauke et al (2010) reported the variant in an additional case. Recently Kapplinger et al (2011) reported this variant in 8 cases of ARVC, though some may overlap with previously reported cases. This variant creates a stop codon 79 residues into the PKP2 protein; it is predicted to either prevent protein production via nonsense mediated mRNA decay or to create a truncated protein. Joshi-Mukherjee et al (2008) studied the variant in neonatal rat ventricular myocytes in culture. They found that a truncated protein was expressed, which failed to localize appropriately and reduced expression of connexin-43 and loss of expression of HSP90. Gerull B et al (2004) did not find the variant in 250 presumably healthy controls of unspecified ethnicity. Klauke et (2010) report that they did not find the variant in 363 control individuals of unspecified race. Christensen et al (2010) did not see the variant in 650 controls. Kapplinger et al did not observe the variant in 427 control individuals. Thus in total this variant has not been observed in at least 1690 control individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 2 of 14 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple individuals and families with arrhythmogenic right ventricular cardiomyopathy and was determined to be a Dutch founder mutation (PMID: 19955750, 15489853, 21301620, 30847666, 31386562, 21606396). Functional studies showed this variant leads to reduced PKP2 expression, poor localization to the cell membrane and altered desmosomal protein interactions (PMID: 19084810, 24704780). Loss-of-function variation in PKP2 is an established mechanism of disease (PMID: 19084810, 15489853). The c.235C>T (p.Arg79Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251328) and thus is presumed to be rare. Based on the available evidence, the c.235C>T (p.Arg79Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 29, 2023	This variant changes 1 nucleotide in exon 2 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Experimental studies have shown that the PKP2 protein expression was decreased by 50% in cells from a heterozygous carrier compared with wild type (PMID: 24704780). It has been shown that the mutant protein does not localize to sites of cell-cell contact and shows reduced ability to interact with connexin 43 protein (PMID: 19084810). This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 19955750, 21301620, 21606396, 24704780, 25765472, 31386562), and is thought to be a founder mutation in the Dutch population (PMID: 21301620). This variant has been identified in 1/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2019

The p.Arg79X variant in PKP2 has been previously identified in >15 individuals with ARVC and segregated with disease in >15 affected individuals from >5 families (Gerull 2004, Dalal 2006, van Tintelen 2006, den Haan 2009, Christensen 2010, van der Zwaag 2010, Larsen 2012, Noorman 2013, Rasmussen 2014, LMM data). This variant has also been identified in 1/111652 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 79, which is predicted to lead to a truncated or absent protein. In vitro functional studies support that this variant results in reduced PKP2 expression (Joshi-Mukherjee 2008). Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The p.R79* pathogenic mutation (also known as c.235C>T), located in coding exon 2 of the PKP2 gene, results from a C to T substitution at nucleotide position 235. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been described in numerous individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was determined to be a Dutch founder mutation associated with reduced penetrance and variable expressivity (van der Zwaag PA et al. Neth Heart J. 2010;18(12):583-91). Functional in vitro analysis demonstrated poor localization to the cell membrane and altered desmosomal protein interactions with reduced expression (Joshi-Mukherjee R et al. Heart Rhythm. 2008;5:1715-1723). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2018

Variant summary: PKP2 c.235C>T (p.Arg79X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.397C>T, p.Gln133X; c.1211dupT, p.Val406fsX4; c.1237C>T, p.Arg413X). The variant allele was found at a frequency of 4.1e-06 in 246126 control chromosomes. c.235C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, including multiple affected individuals from several families, and was reported to be a Dutch founder mutation (Van der Zwaag_PKP2_NethHeartJ_2010). At least one publication reports experimental evidence evaluating an impact on protein function. This report showed the mutant protein failed to preferentially localize to sites of cell-cell apposition, resulted in reduced abundance of Cx43 after R79x expression and prevented its physical interaction with both DP and Cx43 (Joshi-Mukherjee_2008). Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.70
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121434420; hg19: chr12-33031955; COSMIC: COSV50729880;