dbSNP rs794729098: PKP2:p.Cys752Arg (chr12-32796212-A-G) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.2254T>C	p.Cys752Arg	missense_variant	Exon 11 of 13	ENST00000340811.9	NP_001005242.2	Q99959-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 link	c.2254T>C	p.Cys752Arg	missense_variant	Exon 11 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:4

Dec 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1

May 05, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Dec 21, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 16, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.2

.;M

PrimateAI

Uncertain

0.76

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over