NM_001005242.3(PKP2):c.2066_2070del (p.His689fs) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 7, 2023
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:: RCV000850014.11

Allele description [Variation Report for NM_001005242.3(PKP2):c.2066_2070del (p.His689fs)]

NM_001005242.3(PKP2):c.2066_2070del (p.His689fs)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.2066_2070del (p.His689fs)

HGVS:

NC_000012.12:g.32802501_32802505del
NG_009000.1:g.99343_99347del
NM_001005242.3:c.2066_2070delMANE SELECT
NM_004572.4:c.2198_2202del
NP_001005242.2:p.His689fs
NP_004563.2:p.His733fs
LRG_398:g.99343_99347del
NC_000012.11:g.32955435_32955439del
NC_000012.12:g.32802500_32802504delGGTGT
NM_001005242.2:c.2066_2070del
NM_001005242.2:c.2066_2070delACACC
NM_004572.3:c.2198_2202delACACC
p.H689Pfs*8

Protein change:

H689fs

Links:

dbSNP: rs397517021

NCBI 1000 Genomes Browser:

rs397517021

Molecular consequence:

NM_001005242.3:c.2066_2070del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004572.4:c.2198_2202del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000992156	Heart Center, Academic Medical Center Amsterdam	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 1, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV003924230	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004022278	deCODE genetics, Amgen	no assertion criteria provided	Pathogenic (Jul 21, 2023)	germline	research
SCV004183401	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
Icelandic	germline	yes	305	not provided	not provided	not provided	not provided	research

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 Heart Center, Academic Medical Center Amsterdam, SCV000992156.1

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

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003924230.1

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

Description

PKP2 NM_004572.3 exon 11 p.His733Alafs*8 (c.2197_2202delinsG): This variant has been reported in the literature in several individuals with ARVC, segregating with disease in at least 4 affected family members (Syrris 2006 PMID:16415378, den Haan 2009 PMID:20031617, Fressart 2010 PMID:20400443, Xu 2010 PMID:20152563, Walsh 2017 PMID:27532257, Hoorntje 2018 PMID:30161220). This variant is not present in large control databases; of note, another variant with a similar amino acid impact (p.His733Profs*8) is present in 0.003% (5/129074) of European controls in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-32955433-GGGTGT-G). This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:45063). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a deletion of 6 nucleotides and an insertion of 1 nucleotide; this indel creates a premature stop codon 8 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Rasmussen 2014 PMID:24704780). In summary, 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

From deCODE genetics, Amgen, SCV004022278.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Icelandic	305	not provided	not provided	research	not provided

Description

The variant NM_001005242.3:c.2066_2070del (chr12:32802499) in PKP2 was detected in 137 heterozygotes out of 58K WGS Icelanders (MAF= 0,118%). Following imputation in a set of 166K Icelanders (305 imputed heterozygotes) we observed an association with atrial fibrillation and flutter using 20168 cases and 351419 controls (OR= 2.31, P= 2.75e-05) and cardiomyopathy using 1974 cases and 365360 controls (OR= 4.11, P= 1.75e-04). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.

#	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		305	not provided	not provided	not provided

From Baylor Genetics, SCV004183401.1

#	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: May 7, 2024

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