ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1170+4_1170+7del (rs397516988)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183787 SCV000236268 likely pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The c.1170+4_1170+7delAGTG likely pathogenic variant in the PKP2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in several other unrelated individuals with suspected or confirmed ARVC referred for cardiogenetic testing at GeneDx. Yet so far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The c.1170+4_1170+7delAGTG variant results in the deletion of four intronic nucleotides and in silico splicing algorithms predict this variant destroys the natural splice donor site of intron 4 in the PKP2 gene, which may cause abnormal gene splicing. This variant may lead to either an abnormal message which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Multiple other downstream splice site variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, the c.1170+4_1170+7delAGTG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000622167 SCV000734884 uncertain significance Cardiovascular phenotype 2016-05-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001212172 SCV001383748 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-08-30 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein, but it affects a nucleotide within the consensus splice site of the intron. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 45012). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038151 SCV000061817 uncertain significance not specified 2009-05-27 no assertion criteria provided clinical testing

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