rs766209297

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The ENST00000340811.9(PKP2):c.1162C>T(p.Arg388Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,918 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PKP2
ENST00000340811.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.91

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.

PM1

In a repeat ARM 2 (size 39) in uniprot entity PKP2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in ENST00000340811.9

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 12-32868935-G-A is Pathogenic according to our data. Variant chr12-32868935-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32868935-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	4/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	4/13	1	NM_001005242.3	ENSP00000342800	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251320

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460734

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) (MIM#609040). On the other hand, dominant-negative is the proposed mechanism for missense variants in this gene (PMID: 23183494, 24967631). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity. (PMID: 17010805, 23183494). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2+v3: 2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: v2: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Armadillo/beta-catenin-like repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten heterozygous and compound heterozygous individuals with ARVC. It was noted that compound heterozygous individuals presented with an earlier age of onset and severe disease (PMID: 19880068, 20152563, 24967631, 32268277; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 12, 2017	The c.1162C>T (p.Arg388Trp) variant in the PKP2 gene has been observed in two unrelated individuals with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) as well as in three unrelated families affected by ARVC with incomplete penetrance (PMID 19880068, 20152563). Both studies reported that this variant was not observed in a large number of ethnically matched controls. Additionally, the gnomAD database reports this variant in 1 out of 246,082 individuals indicating it is not a common variant in general population. The c.1162C>T (p.Arg388Trp) variant in the PKP2 gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 388 of the PKP2 protein (p.Arg388Trp). This variant is present in population databases (rs766209297, gnomAD 0.003%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 20152563, 24967631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201979). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 10, 2019	- -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This missense variant replaces arginine with tryptophan at codon 388 of the PKP2 protein. Computational tools predict that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant is a recurrent mutation in the South Afrikaner population (PMID 19880068; Machipisa 2016, dissertation, University of Cape Town) and has been observed in seven unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 19880068, 24967631, 28472724, 31319917, 32268277). This variant has been observed in compound heterozygosity with a pathogenic truncation variant in individuals from two different families affected with severe, early-onset arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 20152563). Heterozygous individuals from these families (PMID: 19880068, 20152563) and another unrelated heterozygous adult were reported to be asymptomatic (PMID: 34135346), consistent with low penetrance expected of pathogenic PKP2 variants. This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 10, 2023

This missense variant replaces arginine with tryptophan at codon 388 of the PKP2 protein. Computational tools predict that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant is a recurrent mutation in the South Afrikaner population (PMID 19880068; Machipisa 2016, dissertation, University of Cape Town) and has been observed in seven unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 19880068, 24967631, 28472724, 31319917, 32268277). This variant has been observed in compound heterozygosity with a pathogenic truncation variant in individuals from two different families affected with severe, early-onset arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 20152563). Heterozygous individuals from these families (PMID: 19880068, 20152563) and another unrelated heterozygous adult were reported to be asymptomatic (PMID: 34135346), consistent with low penetrance expected of pathogenic PKP2 variants. This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2012

p.Arg388Trp (CGG>TGG): c.1162 C>T in exon 4 of the PKP2 gene (NM_004572.3). The Arg388Trp mutation in the PKP2 gene has been reported in association with ARVC (Watkins D et al., 2009; Xu T et al., 2010). Watkins et al. identified Arg388Trp in four individuals of European ancestry from South Africa with ARVC and reported the mutation was absent from 241 control individuals of various ethnic backgrounds. Haplotype analysis suggested Arg388Trp may be a founder mutation (Watkins D et al., 2009). One proband in this study was compound heterozygous for Arg388Trp and a frameshift mutation in the PKP2 gene, and compound heterozygous individuals in this family reportedly had a more severe phenotype (Watkins D et al., 2009). Xu et al. also reported two brothers who were compound heterozygous for Arg388Trp and a frameshift mutation in the PKP2 gene, and Arg388Trp was absent from 700 ethnically-matched control alleles. In addition, the NHLBI ESP Exome Variant Server reports Arg388Trp was not observed in approximately 6,400 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations. Therefore, Arg388Trp is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.92

MutPred

0.93

Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);

MVP

0.91

MPC

0.67

ClinPred

0.99

GERP RS

4.0

Varity_R

0.86

gMVP

0.74

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