Submissions for variant NM_001005242.3(PKP2):c.2357+1G>T

dbSNP: rs111517471

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183715	SCV000236193	pathogenic	not provided	2018-04-05	criteria provided, single submitter	clinical testing	c.2489+1 G>T: IVS12+1 G>T in intron 12 of the PKP2 gene (NM_004572.3). The c.2489+1 G>T mutation in the PKP2 gene has been published previously in association with ARVC (DenHaan et al., 2009). The mutation destroys the canonical splice donor site in intron 12 and is expected to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the PKP2 gene have been reported in association with ARVC. In summary, c.2489+1 G>T in the PKP2 gene is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262835	SCV001440850	likely pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001262835	SCV004295863	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031616, 20031617, 21822014, 22214898). ClinVar contains an entry for this variant (Variation ID: 45071). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000183715	SCV005051194	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PM2, PS4:Moderate, PS1:Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038212	SCV000061880	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2009-10-07	no assertion criteria provided	clinical testing