Submissions for variant NM_001005242.3(PKP2):c.1379-2075_1379-2074dup

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003508356	SCV004273478	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-06-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro472Glyfs*49) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551).
Color Diagnostics, LLC DBA Color Health	RCV003534159	SCV004358890	uncertain significance	Cardiomyopathy	2022-11-21	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 | NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 | NM_001005242). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, transcriptional studies have not been reported for this variant, and the functional impact of this variant is unknown. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.