NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 31, 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:: RCV000007146.31

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 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
SCV000027342	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000288604	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17041889, 23911551, 15489853, 19955750, 21301620, 21606396, 28492532
SCV000731253	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-WGS-HudsonAlpha	criteria provided, single submitter (HA_AGHI_assertions_20171208)	Pathogenic (Nov 28, 2017)	unknown	research	Citation Link,
SCV000733170	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000743461	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Oct 8, 2014)	germline	clinical testing	Citation Link,
SCV000840033	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001468665	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 13, 2020)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV002789328	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 25, 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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	2	not provided	not provided	2	not provided	clinical testing, research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	unknown	1	not provided	not provided	1	not provided	research

Citations

PubMed

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

Mechanistic basis of desmosome-targeted diseases.

Al-Jassar C, Bikker H, Overduin M, Chidgey M.

J Mol Biol. 2013 Nov 1;425(21):4006-22. doi: 10.1016/j.jmb.2013.07.035. Epub 2013 Aug 2. Review.

PubMed [citation]

PMID:: 23911551
PMCID:: PMC3807649

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000027342.2

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

Description

In 6 unrelated probands of western European descent, Gerull et al. (2004) found that arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040) was related to a heterozygous 235C-T transition in exon 2 of the PKP2 gene, resulting in an arg79-to-stop (R79X) substitution. At least 1 of the individuals had a positive family history and 1 had left ventricular as well as right ventricular involvement. All were male.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000288604.11

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

Description

This sequence change creates a premature translational stop signal (p.Arg79*) 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 (rs121434420, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 19955750, 21301620, 21606396). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6754). 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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-WGS-HudsonAlpha, SCV000731253.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided
2	not provided	1	not provided	not provided	research	not provided

#	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
2	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733170.1

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

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743461.1

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

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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840033.1

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

Description

A heterozygous c.235C>T (p.R79*) pathogenic variant in the PKP2 gene was detected in this individual. This variant has been previously described in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (PMID 19955750, 15489853, 21301620, 21606396). In addition, experimental studies have shown that this variant results in reduced PKP2 protein expression, a loss of localization to sites of cell-cell contact and reduces interaction with connexin 43 protein in vitro (PMID 19084810). Therefore, we consider this variant to be 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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001468665.1

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

Description

ACMG codes:PVS1, PS4, PS3, PM2, PP1S

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

From Fulgent Genetics, Fulgent Genetics, SCV002789328.1

#	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: Oct 20, 2024

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