NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 17, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000246785.12

Allele description [Variation Report for NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter)]

NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter)

Other names:

p.R79*:CGA>TGA

HGVS:

NC_000012.12:g.32879021G>A
NG_009000.1:g.22826C>T
NM_001005242.3:c.235C>TMANE SELECT
NM_004572.4:c.235C>T
NP_001005242.2:p.Arg79Ter
NP_004563.2:p.Arg79Ter
NP_004563.2:p.Arg79Ter
LRG_398t1:c.235C>T
LRG_398:g.22826C>T
LRG_398p1:p.Arg79Ter
NC_000012.11:g.33031955G>A
NM_004572.3:c.235C>T
NM_004572.4:c.235C>T
c.235C>T
p.Arg79X

Protein change:

R79*; ARG79TER

Links:

OMIM: 602861.0001; dbSNP: rs121434420

NCBI 1000 Genomes Browser:

rs121434420

Molecular consequence:

NM_001005242.3:c.235C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.235C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000318240	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 17, 2021)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 15489853, 16567567, 19084810, 19955750, 20031616, 20829228, 21301620, 22177269, 23178689, 23810883, 23889974, 24704780, 25765472 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000318240

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 17, 2021)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.

Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L.

Nat Genet. 2004 Nov;36(11):1162-4. Epub 2004 Oct 17. Erratum in: Nat Genet. 2005 Jan;37(1):106.

PubMed [citation]

PMID:: 15489853

Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.

van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, van der Smagt J, Boven LG, Mannens MM, van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, van Gelder IC, Hauer RN.

Circulation. 2006 Apr 4;113(13):1650-8. Epub 2006 Mar 27.

PubMed [citation]

PMID:: 16567567

See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000318240.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.R79* pathogenic mutation (also known as c.235C>T), located in coding exon 2 of the PKP2 gene, results from a C to T substitution at nucleotide position 235. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been described in numerous individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was determined to be a Dutch founder mutation associated with reduced penetrance and variable expressivity (van der Zwaag PA et al. Neth Heart J. 2010;18(12):583-91). Functional in vitro analysis demonstrated poor localization to the cell membrane and altered desmosomal protein interactions with reduced expression (Joshi-Mukherjee R et al. Heart Rhythm. 2008;5:1715-1723). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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