NM_001005242.3(PKP2):c.1378+1G>C AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 6, 2024
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:: RCV002513499.4

Allele description [Variation Report for NM_001005242.3(PKP2):c.1378+1G>C]

NM_001005242.3(PKP2):c.1378+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.1378+1G>C

HGVS:

NC_000012.12:g.32850765C>G
NG_009000.1:g.51082G>C
NM_001005242.3:c.1378+1G>CMANE SELECT
NM_001407155.1:c.1378+1G>C
NM_001407156.1:c.1378+1G>C
NM_001407157.1:c.1378+1G>C
NM_001407158.1:c.1051+1G>C
NM_001407159.1:c.1051+1G>C
NM_001407160.1:c.1051+1G>C
NM_001407161.1:c.1378+1G>C
NM_001407162.1:c.1051+1G>C
NM_004572.4:c.1378+1G>C
LRG_398t1:c.1378+1G>C
LRG_398:g.51082G>C
NC_000012.11:g.33003699C>G
NM_004572.3:c.1378+1G>C
c.1378+1G>C

Links:

dbSNP: rs397516994

NCBI 1000 Genomes Browser:

rs397516994

Molecular consequence:

NM_001005242.3:c.1378+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407155.1:c.1378+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407156.1:c.1378+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407157.1:c.1378+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407158.1:c.1051+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407159.1:c.1051+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407160.1:c.1051+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407161.1:c.1378+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407162.1:c.1051+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004572.4:c.1378+1G>C - 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
SCV003474132	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 3, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18662195, 20400443, 31386562, 16199547, 15489853, 23911551, 28492532
SCV005047069	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2024)	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

SCV003474132

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 3, 2022)

germline

clinical testing

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

SCV005047069

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 6, 2024)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations.

Fidler LM, Wilson GJ, Liu F, Cui X, Scherer SW, Taylor GP, Hamilton RM.

J Cell Mol Med. 2009 Oct;13(10):4219-28. doi: 10.1111/j.1582-4934.2008.00438.x. Epub 2008 Jul 26.

PubMed [citation]

PMID:: 18662195
PMCID:: PMC4496128

Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.

Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, et al.

Europace. 2010 Jun;12(6):861-8. doi: 10.1093/europace/euq104. Epub 2010 Apr 16.

PubMed [citation]

PMID:: 20400443

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003474132.2

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

Description

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. ClinVar contains an entry for this variant (Variation ID: 45022). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18662195, 20400443, 31386562). This variant is present in population databases (rs397516994, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 5 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).

#	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 Clinical Genomics Laboratory, Washington University in St. Louis, SCV005047069.1

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

Description

The PKP2 c.1378+1G>C variant has been reported in several individuals affected with ARVC (Costa S et al., PMID: 33238575; Fidler LM et al., PMID: 18662195; Fressart V et al., PMID: 20400443; Medeiros-Domingo A et al., PMID: 27194543; van Lint FHM et al., PMID: 31386562). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by six submitters and is only observed on 1/250,730 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on PKP2 function. Additionally, another variant in the same nucleotide, c.1378+1G>A, has been described in an affected individual and is considered pathogenic (Fidler LM et al., PMID: 18662195, ClinVar Variation ID: 923177). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified 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		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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