ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2578-8T>G (rs794729101)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766582 SCV000236198 uncertain significance not provided 2014-03-28 criteria provided, single submitter clinical testing c.2578-8 T>G: IVS13-8 T>G in intron 13 of the PKP2 gene (NM_004572.3). The c.2578-8 T>G variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. In silico splice prediction algorithms predict c.2578-8 T>G destroys or decreases the efficiency of the canonical splice donor site in intron 13 which could cause abnormal gene splicing. The c.2578-8 T>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other splice site mutations in the PKP2 gene have been reported in association with ARVC. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000529764 SCV000638894 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-07-31 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 201969). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183720 SCV000280415 uncertain significance not specified 2014-04-11 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS13-8 T>G (c.2578-8 T>G) in the PKP2 gene: This is a completely novel splice-site variant. It has not been reported previously as a disease-causing mutation or as a benign polymorphism. In silico splice prediction algorithms predict that it destroys or decreases the efficiency of the canonical splice donor site in intron 13 which could cause abnormal gene splicing. Other splice site mutations in the PKP2 gene have been reported in HGMD in association with ARVC. The variant has not been seen in ~6500 individuals from publicly available population datasets. It is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.

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