Submissions for variant NM_001005242.3(PKP2):c.1170+4_1170+7del

dbSNP: rs397516988

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183787	SCV000236268	likely pathogenic	not provided	2024-10-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31386562)
Ambry Genetics	RCV000622167	SCV000734884	uncertain significance	Cardiovascular phenotype	2016-05-24	criteria provided, single submitter	clinical testing	The c.1170+4_1170+7delAGTG alteration is located in Intron 4 (E) of the PKP2 gene. This alteration consists of a deletion of 4 nucleotides at nucleotide position c.11704 Intron 4 (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001212172	SCV001383748	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs397516988, gnomAD 0.007%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 31386562). ClinVar contains an entry for this variant (Variation ID: 45012). Variants that disrupt 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. 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.
All of Us Research Program, National Institutes of Health	RCV003996364	SCV004832090	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This variant causes a deletion of 4 nucleotides in intron 4 of the PKP2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 31386562). This variant has been identified in 1/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Other variants that are predicted to impact the same intron 4 splice donor site have also been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (MID: 20400443, 26887364, 25611685, 32372669, ClinVar SCV003350423.1, SCV000061816.6). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038151	SCV000061817	uncertain significance	not specified	2009-05-27	no assertion criteria provided	clinical testing