NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter) AND Familial isolated arrhythmogenic right ventricular dysplasia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 30, 2020
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:: RCV001175485.3

Allele description [Variation Report for NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter)]

NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter)

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.1780C>T (p.Gln594Ter)

Other names:

p.Q638*:CAG>TAG

HGVS:

NC_000012.12:g.32822526G>A
NG_009000.1:g.79321C>T
NM_001005242.3:c.1780C>TMANE SELECT
NM_004572.4:c.1912C>T
NP_001005242.2:p.Gln594Ter
NP_004563.2:p.Gln638Ter
NP_004563.2:p.Gln638Ter
LRG_398t1:c.1912C>T
LRG_398:g.79321C>T
LRG_398p1:p.Gln638Ter
NC_000012.11:g.32975460G>A
NM_004572.3:c.1912C>T
c.1912C>T
p.Gln638X

Protein change:

Q594*

Links:

dbSNP: rs397517012

NCBI 1000 Genomes Browser:

rs397517012

Molecular consequence:

NM_001005242.3:c.1780C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.1912C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial isolated arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016342; MedGen: C4274968; OMIM: PS107970

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339078	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 30, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18382419, 15489853, 16101641, 23810883, 24967631, 25525159, 26743238 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001339078

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 30, 2020)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Awad MM, Calkins H, Judge DP.

Nat Clin Pract Cardiovasc Med. 2008 May;5(5):258-67. doi: 10.1038/ncpcardio1182. Epub 2008 Apr 1. Review.

PubMed [citation]

PMID:: 18382419
PMCID:: PMC2822988

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

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339078.1

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

Description

Variant summary: PKP2 c.1912C>T (p.Gln638X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 252142 control chromosomes. c.1912C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Gerull_2004, Wlodarska_2008, Perrin_2013, Alcalde_2014, Adler_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: May 1, 2024

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