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NM_001005242.3(PKP2):c.1378+2T>A AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 13, 2019
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:
RCV001049197.8

Allele description [Variation Report for NM_001005242.3(PKP2):c.1378+2T>A]

NM_001005242.3(PKP2):c.1378+2T>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.1378+2T>A
HGVS:
  • NC_000012.12:g.32850764A>T
  • NG_009000.1:g.51083T>A
  • NM_001005242.3:c.1378+2T>AMANE SELECT
  • NM_001407155.1:c.1378+2T>A
  • NM_001407156.1:c.1378+2T>A
  • NM_001407157.1:c.1378+2T>A
  • NM_001407158.1:c.1051+2T>A
  • NM_001407159.1:c.1051+2T>A
  • NM_001407160.1:c.1051+2T>A
  • NM_001407161.1:c.1378+2T>A
  • NM_001407162.1:c.1051+2T>A
  • NM_004572.4:c.1378+2T>A
  • LRG_398t1:c.1378+2T>A
  • LRG_398:g.51083T>A
  • NC_000012.11:g.33003698A>T
  • NM_004572.3:c.1378+2T>A
Links:
dbSNP: rs762103704
NCBI 1000 Genomes Browser:
rs762103704
Molecular consequence:
  • NM_001005242.3:c.1378+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407155.1:c.1378+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407156.1:c.1378+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407157.1:c.1378+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407158.1:c.1051+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407159.1:c.1051+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407160.1:c.1051+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407161.1:c.1378+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407162.1:c.1051+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_004572.4:c.1378+2T>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001213236Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 13, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213236.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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). 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 not been reported in the literature in individuals with PKP2-related conditions. This variant is present in population databases (rs762103704, ExAC 0.002%). This sequence change affects a donor splice site in intron 5 of the PKP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024