NM_001005242.3(PKP2):c.1170+1G>A AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 15, 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:: RCV000168932.9

Allele description [Variation Report for NM_001005242.3(PKP2):c.1170+1G>A]

NM_001005242.3(PKP2):c.1170+1G>A

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.1170+1G>A

HGVS:

NC_000012.12:g.32868926C>T
NG_009000.1:g.32921G>A
NM_001005242.3:c.1170+1G>AMANE SELECT
NM_001407155.1:c.1170+1G>A
NM_001407156.1:c.1170+1G>A
NM_001407157.1:c.1170+1G>A
NM_001407158.1:c.843+1G>A
NM_001407159.1:c.843+1G>A
NM_001407160.1:c.843+1G>A
NM_001407161.1:c.1170+1G>A
NM_001407162.1:c.843+1G>A
NM_004572.4:c.1170+1G>A
LRG_398t1:c.1170+1G>A
LRG_398:g.32921G>A
NC_000012.11:g.33021860C>T
NM_004572.3:c.1170+1G>A

Links:

dbSNP: rs786204392

NCBI 1000 Genomes Browser:

rs786204392

Molecular consequence:

NM_001005242.3:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407155.1:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407156.1:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407157.1:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407158.1:c.843+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407159.1:c.843+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407160.1:c.843+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407161.1:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407162.1:c.843+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004572.4:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000288588	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 15, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 15489853, 23911551, 20400443, 26887364, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000288588

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 15, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000288588.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 26887364). ClinVar contains an entry for this variant (Variation ID: 188657). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the PKP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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: Sep 29, 2024

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