Submissions for variant NM_001005242.3(PKP2):c.1A>G (p.Met1Val)

dbSNP: rs794729107

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002890496	SCV003243600	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-09-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2038137). This sequence change affects the initiator methionine of the PKP2 mRNA. The next in-frame methionine is located at codon 110. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy (PMID: 24704780). Studies have shown that disruption of the initiator codon alters PKP2 gene expression (PMID: 24704780). This variant disrupts a region of the PKP2 protein in which other variant(s) (p.Ala65Ser) have been observed in individuals with PKP2-related conditions (PMID: 20400443). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002890496	SCV004027707	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-07-24	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_SUP,PM2_SUP