rs397516989

Variant names:

• chr12-32850932-T-TA
• rs397516989
• NM_001005242.3:c.1211dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.1211dupT​(p.Val406SerfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L404L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.45
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 12-32850932-T-TA is Pathogenic according to our data. Variant chr12-32850932-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 45015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1211dupT	p.Val406SerfsTer4	frameshift_variant	Exon 5 of 13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1211dupT	p.Val406SerfsTer4	frameshift_variant	Exon 5 of 13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:4

Sep 21, 2015

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

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

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val406Serfs*4) 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, 17041889, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with arrhythmogenic rightventricular dysplasia/cardiomyopathy and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16567567, 23871674, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as 1211–1212insT (Val406SerfsX3) and c.1211dup p.(Val406fs). ClinVar contains an entry for this variant (Variation ID: 45015). For these reasons, this variant has been classified as Pathogenic. -

Dec 28, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

-

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, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2: PVS1, PM2 -

Cardiomyopathy Pathogenic:1

Mar 17, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 5 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over sixty individuals affected with arrhythmogenic right ventricular cardiomyopathy and is reported as a Dutch founder mutation (e.g., PMID: 20031616, 23871674, 27532257, 37505369). A study of 106 heterozygous carriers has shown that this variant is associated with typical arrhythmogenic right ventricular cardiomyopathy, as well as milder left ventricular involvement (PMID: 37505369). About 44% of the carriers were diagnosed with arrhythmogenic cardiomyopathy, at a mean age of 41 years (PMID: 37505369). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Jan 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val406SerfsX4 variant in PKP2 has been identified in >15 individuals with ARVC, the majority of whom were Dutch (van Tintelen 2006, Groeneweg 2013, Orgero n 2017, Proost 2017, Walsh 2017, LMM data). It was also identified in the homozy gous state in 2 siblings with hypoplastic left heart syndrome (Verhagen 2018). I t was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 406 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of f unction of the PKP2 gene is an established disease mechanism in autosomal domina nt ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP criteria applied: PVS1, PS4, PM2. -

Cardiovascular phenotype Pathogenic:1

Mar 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1211dupT pathogenic mutation, located in coding exon 5 of the PKP2 gene, results from a duplication of T at nucleotide position 1211, causing a translational frameshift with a predicted alternate stop codon (p.V406Sfs*4). This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -

Cardiac arrhythmia Pathogenic:1

Nov 15, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKP2 c.1211dupT (p.Val406SerfsX4) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1613G>A/ p.Trp538X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246050 control chromosomes. This variant has been reported in multiple confirmed ARVD patients, some of whom have a strong family history. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516989; hg19: chr12-33003866;