Submissions for variant NM_001005242.3(PKP2):c.2357+5G>A

dbSNP: rs1555141020

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497496	SCV000590407	likely pathogenic	not provided	2020-01-16	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20573160)
Ambry Genetics	RCV000619521	SCV000734874	uncertain significance	Cardiovascular phenotype	2015-12-26	criteria provided, single submitter	clinical testing	The c.2489+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 of the PKP2 gene. This nucleotide position is highly conserved in available vertebrate species. Based on the BDGP and Human Splicing Finder (HSF) splice site prediction tools, this variant is expected to weaken the native splice donor site efficiency; however, direct experimental evidence is not available (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). This variant has not been described in the literature to date; however, a nearby intronic alteration, c.2489+4A>C, has been reported in Dutch families with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and haplotype and mRNA analyses suggest a possible founder mutation with aberrant splicing (van der Zwaag PA et al. Clin Genet. 2011;79:459-67; van der Smagt JJ et al. Cardiology. 2012;123:181-9). Since supporting evidence is limited at this time, the clinical significance of c.2489+5G>A remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808671	SCV000948785	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2019-06-22	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 432656). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 12 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein, but it affects a nucleotide within the consensus splice site of the intron.