rs372827156

Positions:

• chr12-32850907-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.1237C>T​(p.Arg413*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,952 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: 0.000012 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 1.54

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]

PKP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-32850907-G-A is Pathogenic according to our data. Variant chr12-32850907-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 45016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32850907-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1237C>T	p.Arg413*	stop_gained	5/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1237C>T	p.Arg413*	stop_gained	5/13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251358 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.0000965

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000511 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:4

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg413*) 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 (rs372827156, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 24967631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 45016). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2018	The PKP2 c.1237C>T (p.Arg413Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of available literature, the p.Arg413Ter variant has been reported in a heterozygous state in over ten individuals with arrhythmogenic right ventricular cardiomyopathy and in one individual from a cohort of probands who died from sudden cardiac death (Syrris et al. 2006; den Haan et al. 2009; Fressart et al. 2010; Quarta et al. 2011; Alcade et al. 2014; Philips et al. 2014; Campuzano et al. 2014). The p.Arg413Ter variant was absent from 1500 control subjects and is reported at a frequency of 0.000014 in the African population of the Genome Aggregation Database. Based on the clinical evidence and the potential impact of stop-gained variants, the p.Arg413Ter variant is classified as pathogenic for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 29, 2023	The p.Arg413X variant in PKP2 has been identified in multiple individuals with ARVC and segregated with disease in at least 4 affected relatives from three families (Syrris 2006 PMID: 16415378, Unsold 2006, Unsoeld 2009, den Haan 2009 PMID: 20031617, Fressart 2010 PMID: 20400443, Tan 2010 PMID: 20857253, Quarta 2011 PMID: 21606390, Baskin 2013 PMID: 23812740, Philips 2014 PMID: 24585727, Campuzano 2014 PMID: 25447171, Walsh 2017 PMID: 27532257, LMM data). This variant has also been reported by multiple clinical laboratories in ClinVar (Variation ID 45016) and has been identified in 0.01% (4/41436) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Overexpression of this variant in mice increased right ventricular size and shortened ventricular action potential durations (Unsoeld 2009). This nonsense variant leads to a premature termination codon at position 413, which is predicted to lead to a truncated or absent protein. 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, PS3_Moderate, PM2_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 16, 2024	This variant changes 1 nucleotide in exon 5 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 31319917, 32659924, 34191271). This variant has been shown to segregate with disease in eleven individuals from two families with arrhythmogenic cardiomyopathy (PMID:24967631, 31156706) and has also been observed in an unaffected adult family member who showed cardiac abnormalities (PMID: 31156706). This variant has also been reported in an asymptomatic individual with a family history of sudden cardiac death (PMID: 29997227). This variant has been identified in 4/282766 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 the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	Observed in multiple unrelated patients with ARVC referred for genetic testing at GeneDx and in published literature (Syrris et al., 2006; den Haan et al., 2009; Unsoeld et al., 2009; Fressart et al., 2010; Tan et al., 2010; Quarta et al., 2011; Philips et al., 2014; Alcalde et al., 2014; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21606390, 27831900, 23299917, 25447171, 25637381, 25525159, 24967631, 20031617, 20857253, 20400443, 24585727, 16415378, 27532257, 28471438, 23812740, 32659924, 32372669, 31386562, 31402444, 31156706, 33684294, 26314686, 29997227, 30790397, 28588093, 29606362, 33087929, 32686758, 33232181, 26582918, 27535533) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	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.Arg413Stop (c.1237C>T) in the PKP2 gene. This variant has been reported in 6 unrelated individuals with ARVC (Unsoeld et al 2006, Syrris et al 2006, Wlodarska et al 2008, denHan et al 2009, Fressart et al 2010). Unsoeld et al reported a large family with 10 affected individuals all of which are genotype positive for the variant. Within this family there are 5 cases of sudden cardiac death at an early age. A majority of the deaths occurred during physical activity. The authors suggested there was a gender specific penetrance; they report all males with the variant showed symptoms while only 30 % of females with the variant exhibited symptoms. This is a nonsense variant where an Arginine codon is replaced with a Stop codon. Nonsense and splicing variants in PKP2 are the most frequent cause of ARVC. This particular variant is predicted to cause a truncated plakophilin-2 protein with the last 8 of 10 residue repeats missing from the final protein. Unsoeld et al (2009) created a mouse model overexpressing the p.Arg413Stop variant and recapitulated the morphological and electrophysiological phenotype. Syrris et al (2006) report the absence of the variant in 400 ethnically diverse controls. Wlodarska et al (2008) report not seeing the variant in 200 controls and Fressat et al (2010) did not observe the variant in 600 controls. Kapplinger et al (2011) sequenced the ARVC genes (including PKP2) in 427 presumably healthy controls of various ethnicities and did not report this variant. Thus in total the variant was not present in 1627 presumably healthy controls of mixed ancestry. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This variant changes 1 nucleotide in exon 5 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 31319917, 32659924, 34191271). This variant has been shown to segregate with disease in eleven individuals from two families with arrhythmogenic cardiomyopathy (PMID:24967631, 31156706) and has also been observed in an unaffected adult family member who showed cardiac abnormalities (PMID: 31156706). This variant has also been reported in an asymptomatic individual with a family history of sudden cardiac death (PMID: 29997227). This variant has been identified in 4/282766 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 the available evidence, this variant is classified as Pathogenic. -

PKP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The PKP2 c.1237C>T variant is predicted to result in premature protein termination (p.Arg413*). This variant has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (Syrris et al. 2006. PubMed ID: 16415378; Philips et al. 2014. PubMed ID: 24585727; Table S1A - Walsh et al. 2017. PubMed ID: 27532257) and an individual with sudden unexplained death (Campuzano et al. 2014. PubMed ID: 25447171). This variant has also been reported in multiple unaffected individuals (Natarajan et al. 2016. PubMed ID: 27831900; Haggerty et al. 2018. PubMed ID: 29997227). In ClinVar, this variant has been interpreted as pathogenic by multiple labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/45016/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Loss-of-function variants in PKP2 are a known cause of disease and are expected to be pathogenic (Gerull et al. 2004. PubMed ID: 15489853). Based on the available evidence, this variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The p.R413* pathogenic mutation (also known as c.1237C>T), located in coding exon 5 of the PKP2 gene, results from a C to T substitution at nucleotide position 1237. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been described in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy, and has also been reported to segregate with disease in several families (Syrris P et al. Circulation. 2006;113(3):356-64; den Haan AD et al. Circ Cardiovasc Genet. 2009;2(5):428-35; Unsoeld B et al. Circulation. 2009;120:S618; Fressart V et al. Europace. 2010;12(6):861-8; Quarta G et al. Circulation. 2011;123(23):2701-9; Campuzano O et al. Forensic Sci Int. 2014;245C:30-37; te Riele AS et al. JACC:Clin Electrophysiol. 2015;1(6):551-60; Campuzano O et al. Front Genet. 2019 May;10:450). 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 07, 2021

Variant summary: PKP2 c.1237C>T (p.Arg413X) 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. The variant allele was found at a frequency of 1.2e-05 in 252358 control chromosomes. c.1237C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Syrris_2006, Fressart_2010, den Haan_2009, Tan_2010, Unsoeld_2006, Unsoeld_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in an animal model. The most pronounced variant effect results in a recapitulation of the right ventricular phenotype in a transgenic mouse overexpressing this variant (Unsoeld_2009). Nine 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	0.50	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.78	D
Vest4		0.90
GERP RS		0.089

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: rs372827156; hg19: chr12-33003841;