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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 17, 2021
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:: RCV000244525.4

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000320057	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 17, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18662195, 20400443, 23671136, 23810894, 27194543, 30790397, 31386562, 31402444, 33232181, 33238575 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000320057

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 17, 2021)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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

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 (10)

Details of each submission

From Ambry Genetics, SCV000320057.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The c.1378+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the PKP2 gene. This mutation has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace. 2010; 12:861-8; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013; 6:569-78; Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Costa S et al. J Clin Med, 2020 Nov;9:). In addition, an alteration at the same position, c.1378+1G>A, has also been reported in association with ARVC (Fidler LM J et al. Cell Mol Med. 2009; 13:4219-28). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

#	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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