rs772220644

Positions:

• chr12-32878041-ACG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.837_838delCG​(p.Val280fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.0610

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32878041-ACG-A is Pathogenic according to our data. Variant chr12-32878041-ACG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.837_838delCG	p.Val280fs	frameshift_variant	3/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.837_838delCG	p.Val280fs	frameshift_variant	3/13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 251016 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135686

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461600 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

Gnomad4 AFR AF: 0.0000482

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: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 14, 2021	The c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in at least three individuals (two individuals in digenic heterozygous status with a p.Arg406Gln variant in the DES gene) from the arrhythmogenic right ventricular cardiomyopathy/dysplasia cohorts (PMID: 28069705, 28588093, 30677492) and in one individual from an analytical cross-sectional study screening the ACMG59 gene, whose detailed phenotype is not described (PMID: 35803546). Loss of function variants are well known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Truncating variants downstream of this variant are reported to be pathogenic by several ClinVar submitters (ClinVar ID: 1693180, 1184949, 2040092, 1767649). This variant is found to be rare (2/282412; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by several (5) submitters in the ClinVar database (ClinVar ID: 202015). Therefore, the c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	This sequence change creates a premature translational stop signal (p.Val280Hisfs*55) 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, 23911551). This variant is present in population databases (rs772220644, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). ClinVar contains an entry for this variant (Variation ID: 202015). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 20, 2023	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2019	The p.Val280fs variant in PKP2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/24030 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs772220644) and has been reported in ClinVar (Variantion ID: 202015). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 280 and leads to a premature termination codon 55 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are well-reported in individuals with ARVC (ARVD/C Genetic Variant Database, http://arvcdatabase.info; Human Gene Mutation Database). In summary, although additional studies are required to fully establish its clinical significance, the p.Val280fs variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	The c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in at least three individuals (two individuals in digenic heterozygous status with a p.Arg406Gln variant in the DES gene) from the arrhythmogenic right ventricular cardiomyopathy/dysplasia cohorts (PMID: 28069705, 28588093, 30677492) and in one individual from an analytical cross-sectional study screening the ACMG59 gene, whose detailed phenotype is not described (PMID: 35803546). Loss of function variants are well known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Truncating variants downstream of this variant are reported to be pathogenic by several ClinVar submitters (ClinVar ID: 1693180, 1184949, 2040092, 1767649). This variant is found to be rare (2/282412; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by several (5) submitters in the ClinVar database (ClinVar ID: 202015). Therefore, the c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2021	Identified in a patient with arrhythmogenic right ventricular cardiomyopathy in published literature (Te Riele et al., 2017) and in individuals referred for genetic testing at GeneDx; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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: 30677492, 28069705, 31447099, 31386562, 31402444) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.837_838delCG pathogenic mutation, located in coding exon 3 of the PKP2 gene, results from a deletion of two nucleotides at nucleotide positions 837 to 838, causing a translational frameshift with a predicted alternate stop codon (p.V280Hfs*55). This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Te Riele AS et al. Cardiovasc Res, 2017 Jan;113:102-111; Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6:[ePub ahead of print]). 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

Oct 07, 2024

Variant summary: PKP2 c.837_838delCG (p.Val280HisfsX55) 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. The variant allele was found at a frequency of 4e-06 in 251016 control chromosomes (gnomAD). c.837_838delCG has been reported in the literature in individuals affected with PKP2-related conditions (example: Dries_GM_2021). The following publication has been ascertained in the context of this evaluation (PMID: 34120153). ClinVar contains an entry for this variant (Variation ID: 202015). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs772220644; hg19: chr12-33030975;