Submissions for variant NM_001005242.3(PKP2):c.2167+1G>A

dbSNP: rs794729116

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183774	SCV000236255	pathogenic	not provided	2012-05-01	criteria provided, single submitter	clinical testing	c.2299+1 G>A: IVS11+1 G>A in intron 11 of the PKP2 gene (NM_004572.3). The c.2299+1 G>A mutation in the PKP2 gene has also not been reported previously as a disease-causing mutation, however this mutation destroys the consensus splice donor site of intron 11 and is expected to cause abnormal gene splicing. Three splice prediction algorithms concur that c.2299+1 G>A results in the loss of the normal splice donor site. This mutation is predicted to lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, other splice site mutations (c.2489+1 G>A, c.2489+4 C>A) in the PKP2 gene have been reported in association with ARVC (Van der Zwaag P et al., 2009). Therefore, c.2299+1 G>A in the PKP2 gene is interpreted to be a disease-causing mutation. The variant is found in ARVC panel(s).
Ambry Genetics	RCV000622076	SCV000737878	likely pathogenic	Cardiovascular phenotype	2024-07-10	criteria provided, single submitter	clinical testing	The c.2299+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 11 of the PKP2 gene. This variant was reported in individuals with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, details were limited (Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000183774	SCV000748029	pathogenic	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517817	SCV002950501	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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, 17041889, 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: 26743238, 36138163). ClinVar contains an entry for this variant (Variation ID: 202005). 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.
Color Diagnostics, LLC DBA Color Health	RCV003532042	SCV004358851	likely pathogenic	Cardiomyopathy	2023-05-23	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 11 of the PKP2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in a few individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238, 36138163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996842	SCV004814333	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-04-15	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in at least two patients with cardiac arrest and/or referred to an inherited arrhythmia clinic (PMID: 26743238, 36138163). The PKP2 c.2299+1G>A variant co-occurred with a pathogenic DSG2 variant in one proband and with a MYH11 variant of uncertain significance in another proband, and it was observed in several asymptomatic family members (PMID: 36138163). The PKP2 c.2299+1G>A variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996842	SCV004848076	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2017-06-12	criteria provided, single submitter	clinical testing	The c.2299+1G>A variant in PKP2 has not been previously reported in individuals with cardiomyopathy or in large population studies, but has been reported in ClinVar (Variation ID: 202005). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splicing variants and other truncating variants in PKP2 are an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.2299+1G>A variant is likely pathogenic.