ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1379-1G>A (rs139159464)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 ( but without additional information. It has also been identified in 0.14% (32/23970) of African chromosomes by the Genome Aggreg ation Consortium (gnomAD,; 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.
Invitae RCV000457984 SCV000557318 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000038162 SCV000920006 uncertain significance not specified 2018-05-08 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. Although, exon 6 is naturally spliced out (Gandjbakhch_2011), the alteration of canonical site may potentially lead to either its full or partial inclusion, leading to a frameshift. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 2.15 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). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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