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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 15, 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:: RCV000038161.9

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]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061827	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Aug 9, 2010)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20400443, 18662195, 24033266
SCV000207152	Blueprint Genetics	no assertion criteria provided	Likely pathogenic (Apr 25, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004825866	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (24) [See all records that cite these PMIDs] 15489853, 16199547, 17010805, 18662195, 19358943, 20152563, 20400443, 23671136, 23810883, 23810894, 23911551, 24704780, 25820315, 26701096, 27194543, 28588093, 29038103, 30677492, 30830208, 33238575, 33968641, 34120153, 34469894, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061827

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Aug 9, 2010)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000207152

Blueprint Genetics

no assertion criteria provided

Likely pathogenic
(Apr 25, 2014)

germline

clinical testing

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

SCV004825866

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 15, 2023)

germline

clinical testing

PubMed (24)
[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	2	not provided	not provided	108544	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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 (25)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061827.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Blueprint Genetics, SCV000207152.1

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

From All of Us Research Program, National Institutes of Health, SCV004825866.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (24)

Description

The c.1378+1G>C intronic variant of the PKP2 gene is located at the canonical donor splice site of intron 5. This variant has been reported in numerous (>15) individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 27194543, 23810894, 23671136, 20400443, 33968641, 28588093, 30830208, 34469894, 30677492, 24704780, 23810883, 25820315). This variant was also identified in the proband, mother and brother in a family, while the mother and brother were asymptomatic carriers (PMID: 33238575). An alteration at the same position, c.1378+1G>A, has also been reported to cause ARVC (PMID:18662195). In-silico computational prediction tools suggest that the c.1378+1G>C variant likely leads to donor loss and disturbs normal splicing, resulting in an absent of disrupted protein product (PMID: 16199547). Loss of function variants are known to be pathogenic for PKP2 gene (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC/D (PMID: 26701096, 15489853, 17010805, 19358943, 20152563) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 517335, 202019, 202035). This variant is found to be rare (1/250730; 0.000003988) in the general population database, gnomAD and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 45022). Therefore, the c.1378+1G>C variant in the PKP2 gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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