NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 13, 2019
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:: RCV000211843.14

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]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061874	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 13, 2019)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 21301620, 19955750, 20031617, 22177269, 23178689, 24704780, 16567567, 15489853, 19084810, 16549640, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061874

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Feb 13, 2019)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	32	10	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia.

van der Zwaag PA, Cox MG, van der Werf C, Wiesfeld AC, Jongbloed JD, Dooijes D, Bikker H, Jongbloed R, Suurmeijer AJ, van den Berg MP, Hofstra RM, Hauer RN, Wilde AA, van Tintelen JP.

Neth Heart J. 2010 Dec;18(12):583-91.

PubMed [citation]

PMID:: 21301620
PMCID:: PMC3018603

Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

Christensen AH, Benn M, Tybjaerg-Hansen A, Haunso S, Svendsen JH.

Cardiology. 2010;115(2):148-54. doi: 10.1159/000263456. Epub 2009 Dec 3.

PubMed [citation]

PMID:: 19955750

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061874.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	32	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Arg79X variant in PKP2 has been previously identified in >15 individuals with ARVC and segregated with disease in >15 affected individuals from >5 families (Gerull 2004, Dalal 2006, van Tintelen 2006, den Haan 2009, Christensen 2010, van der Zwaag 2010, Larsen 2012, Noorman 2013, Rasmussen 2014, LMM data). This variant has also been identified in 1/111652 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 79, which is predicted to lead to a truncated or absent protein. In vitro functional studies support that this variant results in reduced PKP2 expression (Joshi-Mukherjee 2008). Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2.

#	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		32	not provided	10	not provided

Last Updated: Oct 20, 2024

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