NM_001005242.3(PKP2):c.1237C>T (p.Arg413Ter) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000471559.18

Allele description [Variation Report for NM_001005242.3(PKP2):c.1237C>T (p.Arg413Ter)]

NM_001005242.3(PKP2):c.1237C>T (p.Arg413Ter)

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.1237C>T (p.Arg413Ter)

Other names:

p.R413*:CGA>TGA

HGVS:

NC_000012.12:g.32850907G>A
NG_009000.1:g.50940C>T
NM_001005242.3:c.1237C>TMANE SELECT
NM_004572.4:c.1237C>T
NP_001005242.2:p.Arg413Ter
NP_001005242.2:p.Arg413Ter
NP_004563.2:p.Arg413Ter
NP_004563.2:p.Arg413Ter
LRG_398t1:c.1237C>T
LRG_398:g.50940C>T
LRG_398p1:p.Arg413Ter
NC_000012.11:g.33003841G>A
NM_001005242.2:c.1237C>T
NM_004572.3:c.1237C>T
c.1237C>T
p.Arg413X

Protein change:

R413*

Links:

dbSNP: rs372827156

NCBI 1000 Genomes Browser:

rs372827156

Molecular consequence:

NM_001005242.3:c.1237C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.1237C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 9 (ARVD9)
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9; Arrhythmogenic right ventricular cardiomyopathy, type 9; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9
Identifiers:: MONDO: MONDO:0012180; MedGen: C1836906; OMIM: 609040

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545238	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15489853, 17041889, 23911551, 20400443, 20857253, 21606390, 24967631, 28492532
SCV000915591	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 29, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20400443, 16415378, 20031617, 25447171, 24585727, 21606390, 24967631 Citation Link,
SCV001192819	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 14, 2020)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002810385	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	1	not provided	clinical testing, research
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

Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.

Awad MM, Dalal D, Tichnell C, James C, Tucker A, Abraham T, Spevak PJ, Calkins H, Judge DP.

Hum Mutat. 2006 Nov;27(11):1157.

PubMed [citation]

PMID:: 17041889
PMCID:: PMC2799897

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000545238.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg413*) 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 present in population databases (rs372827156, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 24967631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 45016). For these reasons, this variant has been classified as Pathogenic.

#	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

From Illumina Laboratory Services, Illumina, SCV000915591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The PKP2 c.1237C>T (p.Arg413Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of available literature, the p.Arg413Ter variant has been reported in a heterozygous state in over ten individuals with arrhythmogenic right ventricular cardiomyopathy and in one individual from a cohort of probands who died from sudden cardiac death (Syrris et al. 2006; den Haan et al. 2009; Fressart et al. 2010; Quarta et al. 2011; Alcade et al. 2014; Philips et al. 2014; Campuzano et al. 2014). The p.Arg413Ter variant was absent from 1500 control subjects and is reported at a frequency of 0.000014 in the African population of the Genome Aggregation Database. Based on the clinical evidence and the potential impact of stop-gained variants, the p.Arg413Ter variant is classified as pathogenic for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT, SCV001192819.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

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

From Fulgent Genetics, Fulgent Genetics, SCV002810385.1

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

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

Last Updated: Apr 20, 2024

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