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NM_001005242.3(PKP2):c.2254T>C (p.Cys752Arg) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 21, 2022
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:
RCV003165405.2

Allele description

NM_001005242.3(PKP2):c.2254T>C (p.Cys752Arg)

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.2254T>C (p.Cys752Arg)
Other names:
p.C796R:TGT>CGT
HGVS:
  • NC_000012.12:g.32796212A>G
  • NG_009000.1:g.105635T>C
  • NM_001005242.3:c.2254T>CMANE SELECT
  • NM_004572.4:c.2386T>C
  • NP_001005242.2:p.Cys752Arg
  • NP_004563.2:p.Cys796Arg
  • NP_004563.2:p.Cys796Arg
  • LRG_398t1:c.2386T>C
  • LRG_398:g.105635T>C
  • LRG_398p1:p.Cys796Arg
  • NC_000012.11:g.32949146A>G
  • NM_004572.3:c.2386T>C
  • Q99959:p.Cys796Arg
Protein change:
C752R
Links:
UniProtKB: Q99959#VAR_021151; dbSNP: rs794729098
NCBI 1000 Genomes Browser:
rs794729098
Molecular consequence:
  • NM_001005242.3:c.2254T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004572.4:c.2386T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003866305Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Dec 21, 2022) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 (7)

Details of each submission

From Ambry Genetics, SCV003866305.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.C796R pathogenic mutation (also known as c.2386T>C), located in coding exon 12 of the PKP2 gene, results from a T to C substitution at nucleotide position 2386. The cysteine at codon 796 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), noting it as a founder mutation in the Dutch population (Gerull B et al. Nat Genet, 2004 Nov;36:1162-4; van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Campian ME et al. Eur J Nucl Med Mol Imaging, 2010 Nov;37:2079-85; Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11; Noorman M et al. Heart Rhythm, 2013 Feb;10:283-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Svensson A et al. Cardiology, 2021 Sep;146:763-771). Additionally, an in vitro study showed this alteration leads to protein instability and degradation (Kirchner F et al. Circ Cardiovasc Genet, 2012 Aug;5:400-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 28, 2024