Submissions for variant NM_001005242.3(PKP2):c.1378+1G>C

dbSNP: rs397516994

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038161	SCV000061827	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2010-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000183806	SCV000236287	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease AND Non-canonical splice site variant demonstrated to result in loss-of-function (ref); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23671136, 27194543, 20400443, 23810894, 23810883, 30790397, 31386562, 31402444, 33238575, 30677492, 33232181)
Ambry Genetics	RCV000244525	SCV000320057	pathogenic	Cardiovascular phenotype	2021-09-17	criteria provided, single submitter	clinical testing	The c.1378+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the PKP2 gene. This mutation has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace. 2010; 12:861-8; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013; 6:569-78; Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Costa S et al. J Clin Med, 2020 Nov;9:). In addition, an alteration at the same position, c.1378+1G>A, has also been reported in association with ARVC (Fidler LM J et al. Cell Mol Med. 2009; 13:4219-28). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000183806	SCV001447391	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513499	SCV003474132	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-06-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 45022). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18662195, 20400443, 31386562). This variant is present in population databases (rs397516994, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 5 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).
All of Us Research Program, National Institutes of Health	RCV000038161	SCV004825866	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-12-15	criteria provided, single submitter	clinical testing	The c.1378+1G>C intronic variant of the PKP2 gene is located at the canonical donor splice site of intron 5. This variant has been reported in numerous (>15) individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 27194543, 23810894, 23671136, 20400443, 33968641, 28588093, 30830208, 34469894, 30677492, 24704780, 23810883, 25820315). This variant was also identified in the proband, mother and brother in a family, while the mother and brother were asymptomatic carriers (PMID: 33238575). An alteration at the same position, c.1378+1G>A, has also been reported to cause ARVC (PMID:18662195). In-silico computational prediction tools suggest that the c.1378+1G>C variant likely leads to donor loss and disturbs normal splicing, resulting in an absent of disrupted protein product (PMID: 16199547). Loss of function variants are known to be pathogenic for PKP2 gene (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC/D (PMID: 26701096, 15489853, 17010805, 19358943, 20152563) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 517335, 202019, 202035). This variant is found to be rare (1/250730; 0.000003988) in the general population database, gnomAD and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 45022). Therefore, the c.1378+1G>C variant in the PKP2 gene is classified as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV002513499	SCV005047069	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-03-06	criteria provided, single submitter	clinical testing	The PKP2 c.1378+1G>C variant has been reported in several individuals affected with ARVC (Costa S et al., PMID: 33238575; Fidler LM et al., PMID: 18662195; Fressart V et al., PMID: 20400443; Medeiros-Domingo A et al., PMID: 27194543; van Lint FHM et al., PMID: 31386562). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by six submitters and is only observed on 1/250,730 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on PKP2 function. Additionally, another variant in the same nucleotide, c.1378+1G>A, has been described in an affected individual and is considered pathogenic (Fidler LM et al., PMID: 18662195, ClinVar Variation ID: 923177). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Blueprint Genetics	RCV000038161	SCV000207152	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2014-04-25	no assertion criteria provided	clinical testing