rs766209297

chr12-32868935-G-Achr12-32868935-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_001005242.3(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 NM_001005242.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.91

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.

• 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 NM_001005242.3
• 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	UniProt
PKP2	NM_001005242.3	c.1162C>T	p.Arg388Trp	missense_variant	4/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1162C>T	p.Arg388Trp	missense_variant	4/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33

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: 1 AN: 251320 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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: 14 AN: 1460734 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726700

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: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

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: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 10, 2019	- -
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	Invitae	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. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 18, 2015	- -

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	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
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	D
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

Other links and lift over

dbSNP: rs766209297; hg19: chr12-33021869; COSMIC: COSV99298059;