Submissions for variant NM_001005242.3(PKP2):c.1170+2T>A

dbSNP: rs397516987

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038150	SCV000061816	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2013-02-20	criteria provided, single submitter	clinical testing	The 1170+2T>A variant in PKP2 has not been reported in the literature, but has b een identified by our laboratory in 1 individual with ARVC and segregated with d isease in 1 affected relative (LMM unpublished data). This variant has also not been identified in large European American and African American populations by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which incr eases the likelihood that it is pathogenic. However, we cannot exclude that it m ay be common in other populations. This variant occurs in the invariant region ( +/- 1,2) of the splice consensus sequence and is predicted to cause altered spli cing leading to an abnormal or absent protein. In summary, this variant is likel y to be pathogenic, though additional studies are required to fully establish it s clinical significance.
GeneDx	RCV000183737	SCV000236217	pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Reported in association with ARVC in published literature and by another clinical laboratory in ClinVar, and segregated with disease in at least one relative (ClinVar SCV000061816.6; ClinVar; Smith et al., 2020); Identified in a 53-year-old individual with hypertrophic cardiomyopathy in published literature (Alfares et al., 2015); however, a pathogenic variant in the MYH7 gene was also identified, and further details regarding follow-up cardiac investigations and segregation studies were not available.; Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 32372669, 25611685)
Ambry Genetics	RCV002326740	SCV002631612	pathogenic	Cardiovascular phenotype	2021-11-05	criteria provided, single submitter	clinical testing	The c.1170+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 4 in the PKP2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Another alteration impacting the same donor site (c.1170+1G>A) has been described in a patient with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513498	SCV003440443	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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 or hypertrophic cardiomyopathy (PMID: 20400443, 25611685, 32372669; internal data). ClinVar contains an entry for this variant (Variation ID: 45011). 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.