rs794729098

Positions:

• chr12-32796212-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001005242.3(PKP2):​c.2254T>C​(p.Cys752Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,730 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.03

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 12-32796212-A-G is Pathogenic according to our data. Variant chr12-32796212-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 201965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32796212-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2254T>C	p.Cys752Arg	missense_variant	11/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2254T>C	p.Cys752Arg	missense_variant	11/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461730 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 796 of the PKP2 protein (p.Cys796Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 21636032, 23871674). It is commonly reported in individuals of Dutch ancestry (PMID: 21636032, 23871674). ClinVar contains an entry for this variant (Variation ID: 201965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PKP2 function (PMID: 22781308, 23863954). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2023	A functional study examining both in vitro and in vivo effects of the p.(C796R) variant demonstrated protein instability and degradation via calpain proteases, suggesting haploinsufficiency as the mechanism of disease (Kirchner et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34120153, 15489853, 23889974, 21553091, 26082552, 21636032, 23147395, 26585103, 29456632, 28492532, 23863954, 31737537, 30847666, 31386562, 31402444, 23871674, 25820315, 33662488, 21606396, 22781308, 34469894, 23085127, 16567567) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 05, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The p.C796R pathogenic mutation (also known as c.2386T>C), located in coding exon 12 of the PKP2 gene, results from a T to C substitution at nucleotide position 2386. The cysteine at codon 796 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), noting it as a founder mutation in the Dutch population (Gerull B et al. Nat Genet, 2004 Nov;36:1162-4; van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Campian ME et al. Eur J Nucl Med Mol Imaging, 2010 Nov;37:2079-85; Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11; Noorman M et al. Heart Rhythm, 2013 Feb;10:283-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Svensson A et al. Cardiology, 2021 Sep;146:763-771). Additionally, an in vitro study showed this alteration leads to protein instability and degradation (Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, 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

Jan 16, 2023

Variant summary: PKP2 c.2386T>C (p.Cys796Arg) results in a non-conservative amino acid change located in the armadillo domain (Kirchner_2012) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.2386T>C has been reported in the literature in numerous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and has been reported as a Dutch founder mutation (eg. Kirchner_2012, Cox_2011, Groeneweg_2015, etc). In vitro expression studies demonstrated that the the variant leads to protein instability and degradation involving calpain proteases as well as affecting protein folding, and altering the normal cell membrane localization (Kirchner_2012, Gerull_2013). Three 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;D
Vest4		0.93
MutPred		0.96		.;Gain of methylation at C796 (P = 0.0553);
MVP		0.89
MPC		0.84
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.84

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: rs794729098; hg19: chr12-32949146;