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NM_001005242.3(PKP2):c.1379-2109G>A AND not specified

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Sep 25, 2019
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:
RCV000038162.9

Allele description [Variation Report for NM_001005242.3(PKP2):c.1379-2109G>A]

NM_001005242.3(PKP2):c.1379-2109G>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.1379-2109G>A
HGVS:
  • NC_000012.12:g.32843314C>T
  • NG_009000.1:g.58533G>A
  • NM_001005242.3:c.1379-2109G>AMANE SELECT
  • NM_001407155.1:c.1379-2109G>A
  • NM_001407156.1:c.1379-2109G>A
  • NM_001407157.1:c.1379-1G>A
  • NM_001407158.1:c.1052-2109G>A
  • NM_001407159.1:c.1052-2109G>A
  • NM_001407160.1:c.1052-2109G>A
  • NM_001407161.1:c.1379-2109G>A
  • NM_001407162.1:c.1052-2109G>A
  • NM_004572.4:c.1379-1G>A
  • LRG_398t1:c.1379-1G>A
  • LRG_398:g.58533G>A
  • NC_000012.11:g.32996248C>T
  • NM_004572.3:c.1379-1G>A
  • c.1379-1G>A
Links:
dbSNP: rs139159464
NCBI 1000 Genomes Browser:
rs139159464
Molecular consequence:
  • NM_001005242.3:c.1379-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407155.1:c.1379-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407156.1:c.1379-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407158.1:c.1052-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407159.1:c.1052-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407160.1:c.1052-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407161.1:c.1379-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407162.1:c.1052-2109G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407157.1:c.1379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_004572.4:c.1379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061828Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Uncertain significance
(Jul 5, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000920006Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Sep 25, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical 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

Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy.

Gandjbakhch E, Charron P, Fressart V, Lorin de la Grandmaison G, Simon F, Gary F, Vite A, Hainque B, Hidden-Lucet F, Komajda M, Villard E.

Heart. 2011 May;97(10):844-9. doi: 10.1136/hrt.2010.205880. Epub 2011 Mar 3.

PubMed [citation]
PMID:
21378009
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061828.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

Variant classified as Uncertain Significance - Favor Benign. The c.1379-1G>A var iant in PKP2 has been identified by our laboratory in 1 Black individual with mi ld LVH, NSVT, and AFib and a family history of DCM and is listed in the ARVC Dat abase (http://arvcdatabase.info) but without additional information. It has also been identified in 0.14% (32/23970) of African chromosomes by the Genome Aggreg ation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139159464). PKP2 has two isoforms: a short isoform (PKP2a) missing exon 6 and a long isoform (PKP2b) including exon 6. The short isoform is the predominant form in the hear t, and variants in exon 6 may not be associated with ARVC (Gandjbakhch, 2011). T his variant occurs in the invariant region (+/- 1,2) of the splice consensus seq uence of intron 5 and is predicted to cause altered splicing of exon 6. In summa ry, while the clinical significance of the 1379-1G>A variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS 1_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920006.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: PKP2 c.1379-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. In addition, exon 6 is naturally spliced out (Gandjbakhch_2011), suggesting this variant is not damaging. The observed variant frequency within African control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1379-1G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Kapplinger_2011, Dueker_2018, Haggerty_2017, Kobayashi_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite the variant once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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

Last Updated: Feb 1, 2025