Submissions for variant NM_001005242.3(PKP2):c.1379-2109G>A

gnomAD frequency: 0.00050  dbSNP: rs139159464

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038162	SCV000061828	uncertain significance	not specified	2018-07-05	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457984	SCV000557318	likely benign	Arrhythmogenic right ventricular dysplasia 9	2023-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038162	SCV000920006	uncertain significance	not specified	2019-09-25	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV001178106	SCV001342462	likely benign	Cardiomyopathy	2018-11-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000457984	SCV002049509	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-05-22	criteria provided, single submitter	clinical testing	The PKP2 c.1379-1G>A variant (rs139159464) is reported in the literature in a control individual from a cardiomyopathy cohort (Kapplinger 2011). This variant is reported in ClinVar (Variation ID: 45023), and is found in the African population with an allele frequency of 0.15% (38/24900 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 5, which is likely to cause exon skipping, but would leave the transcript in frame. However, without functional studies, the effect on splicing is uncertain. Additionally, the predominant isoform in the heart does not include exon 6, and variants in exon 6 may not be associated with disease (Gandjbakhch 2011). Given the lack of clinical and functional data, the significance of the c.1379-1G>A variant is uncertain at this time. References: Gandjbakhch E et al. Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy. Heart. 2011 May;97(10):844-9. Kapplinger JD et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol. 2011 Jun 7;57(23):2317-27.
Ambry Genetics	RCV002381309	SCV002698178	likely benign	Cardiovascular phenotype	2019-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000457984	SCV003920325	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-03-30	criteria provided, single submitter	clinical testing	PKP2 NM_004572.3 exon 6 c.1379-1G>A: This variant has been reported in the literature in two individuals who underwent exome sequencing, but neither had a diagnosis or features of ARVC (Haggerty 2017 PMID:28471438). This variant is present in 0.1% (38/24900) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-32996248-C-T). This variant is also present in ClinVar (Variation ID:45023). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2). Loss of function variants are a known mechanism of disease for this gene (Rasmussen 2014 PMID:24704780). However, exon 6 does not appear to be spliced in/a coding exon with a different transcript, and there is no additional evidence suggesting pathogenicity at this time. Further studies are needed to understand the impact of this variant. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.