NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Aug 1, 2022
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:: RCV000183722.39

Allele description

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000236200	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 17, 2022)	germline	clinical testing	Citation Link,
SCV000280413	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Jul 29, 2014)	germline	clinical testing
SCV000860205	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Mar 13, 2018)	germline	clinical testing	Citation Link,
SCV001919298	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001955175	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002009819	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002497214	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	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	germline	not provided	10	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000236200.14

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant reduces the expression level of plakophilin and alters desmosomal protein-protein interactions (Joshi-Mukherjee et al., 2008; Rasmussen et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31386562, 23810883, 24704780, 15489853, 16549640, 16567567, 20031617, 19955750, 21301620, 20829228, 22177269, 24125834, 25765472, 26800703, 21606396, 27532257, 20857253, 28152038, 23889974, 23178689, 30847666, 31737537, 31447099, 31402444, 20031616, 19084810, 33662488, 33232181, 32372669, 32522011, 31729605, 33500567)

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280413.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg79Stop (c.235 C>T) in the PKP2 gene. This variant has been reported in at least 20 unrelated individuals with ARVC. The variant was first reported by Gerull et al (2004) in six unrelated individuals with ARVC. Van Tintelen et al (2006) then reported the variant in five unrelated individuals with ARVC. The same group later published 12 unrelated ARVC cases with the variant (including some of their original cases) (van der Zwaag et al 2010). Haplotype analysis supported a founder effect. The authors provide segregation data for 8 families with 2-3 affected individuals with the variant in each family. There were no individuals with definite or probable ARVC who did not have the variant. Christensen et al (2010) reported another patient with ARVC and this variant. Klauke et al (2010) reported the variant in an additional case. Recently Kapplinger et al (2011) reported this variant in 8 cases of ARVC, though some may overlap with previously reported cases. This variant creates a stop codon 79 residues into the PKP2 protein; it is predicted to either prevent protein production via nonsense mediated mRNA decay or to create a truncated protein. Joshi-Mukherjee et al (2008) studied the variant in neonatal rat ventricular myocytes in culture. They found that a truncated protein was expressed, which failed to localize appropriately and reduced expression of connexin-43 and loss of expression of HSP90. Gerull B et al (2004) did not find the variant in 250 presumably healthy controls of unspecified ethnicity. Klauke et (2010) report that they did not find the variant in 363 control individuals of unspecified race. Christensen et al (2010) did not see the variant in 650 controls. Kapplinger et al did not observe the variant in 427 control individuals. Thus in total this variant has not been observed in at least 1690 control individuals.

#	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		10	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000860205.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919298.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955175.1

#	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 Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009819.3

#	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	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV002497214.17

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

PKP2: PVS1, PM2, PS4:Supporting

#	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		3	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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