NM_001005242.3(PKP2):c.1881del (p.Lys628fs) AND Cardiac arrhythmia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 2, 2018
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:: RCV001842942.9

Allele description [Variation Report for NM_001005242.3(PKP2):c.1881del (p.Lys628fs)]

NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

HGVS:

NC_000012.12:g.32821491del
NG_009000.1:g.80359del
NM_001005242.3:c.1881delMANE SELECT
NM_004572.4:c.2013del
NP_001005242.2:p.Lys628fs
NP_004563.2:p.Lys672fs
NP_004563.2:p.Lys672fs
LRG_398t1:c.2013del
LRG_398:g.80359del
LRG_398p1:p.Lys672fs
NC_000012.11:g.32974422del
NC_000012.11:g.32974425del
NC_000012.12:g.32821488delG
NM_004572.3:c.2013del
NM_004572.3:c.2013delC
p.K672RfsX12

Protein change:

K628fs

Links:

dbSNP: rs764817683

NCBI 1000 Genomes Browser:

rs764817683

Molecular consequence:

NM_001005242.3:c.1881del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004572.4:c.2013del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000918022	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 2, 2018)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17010805, 16549640, 20031617, 23354045, 25971409, 28097316, 29221435, 24768880, 20857253, 21723241 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000918022

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 2, 2018)

germline

clinical testing

PubMed (10)
[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

Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Dalal D, James C, Devanagondi R, Tichnell C, Tucker A, Prakasa K, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP.

J Am Coll Cardiol. 2006 Oct 3;48(7):1416-24. Epub 2006 Sep 12.

PubMed [citation]

PMID:: 17010805

Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2.

Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, Prakasa K, Towbin JA, Marcus FI, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP.

Circulation. 2006 Apr 4;113(13):1641-9. Epub 2006 Mar 20.

PubMed [citation]

PMID:: 16549640

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918022.1

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

Description

Variant summary: The PKP2 c.2013delC (p.Lys672ArgfsX12) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2197_2202delinsG, p.His733fsX8; ). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/247018 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). The variant has been reported in numerous affected individuals and families, and has been reported to segregate in families with ARVD, albeit with less than full penetrance (Dalal_2006, Konig_2017, Arbustini_2014). A functional study has shown the variant leads to undetectable mutant cDNA levels indicating instability and degredation (Kim_2013). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is 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: Oct 13, 2024

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