NM_001005242.3(PKP2):c.1557-1G>C AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 28, 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:: RCV000702665.10

Allele description [Variation Report for NM_001005242.3(PKP2):c.1557-1G>C]

NM_001005242.3(PKP2):c.1557-1G>C

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.1557-1G>C

HGVS:

NC_000012.12:g.32824163C>G
NG_009000.1:g.77684G>C
NM_001005242.3:c.1557-1G>CMANE SELECT
NM_001407155.1:c.1557-1G>C
NM_001407156.1:c.1557-1G>C
NM_001407157.1:c.1689-1G>C
NM_001407158.1:c.1230-1G>C
NM_001407159.1:c.1230-1G>C
NM_001407160.1:c.1230-1G>C
NM_001407161.1:c.1557-1G>C
NM_001407162.1:c.1230-1G>C
NM_004572.4:c.1689-1G>C
LRG_398t1:c.1689-1G>C
LRG_398:g.77684G>C
NC_000012.11:g.32977097C>G
NM_004572.3:c.1689-1G>C

Links:

dbSNP: rs78897684

NCBI 1000 Genomes Browser:

rs78897684

Molecular consequence:

NM_001005242.3:c.1557-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407155.1:c.1557-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407156.1:c.1557-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407157.1:c.1689-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407158.1:c.1230-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407159.1:c.1230-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407160.1:c.1230-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407161.1:c.1557-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407162.1:c.1230-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004572.4:c.1689-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000831528	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16199547, 15489853, 23911551, 19863551, 20400443, 27532257, 28492532
SCV003932172	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000831528

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 28, 2023)

germline

clinical testing

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

SCV003932172

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 6, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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 (8)

Details of each submission

From Invitae, SCV000831528.6

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

Description

This sequence change affects an acceptor splice site in intron 7 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs78897684, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 19863551, 20400443, 27532257). This variant is also known as 1690-1G>C. ClinVar contains an entry for this variant (Variation ID: 201989). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003932172.1

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

Description

PVS1, PM2, PS4_supporting

#	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: Apr 20, 2024

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