ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2489+5G>A (rs1555141020)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619521 SCV000734874 uncertain significance Cardiovascular phenotype 2015-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000497496 SCV000590407 likely pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing Although the c.2489+5 G>A likely pathogenic variant has not been reported as a pathogenic or benign to our knowledge, several in silico splice algorithms predict that it significantly reduces or destroys the canonical splice donor site in intron 12 and may cause abnormal gene splicing. Other splice site variants in the PKP2 gene, including two that affect the same canonical splice donor site (c.2489+1 G>A, c.2489+1 G>T) have been reported in the Human Gene Mutation Database in association with ARVD/C (Stenson et al., 2014). Furthermore, the c.2489+5 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000808671 SCV000948785 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-09-12 criteria provided, single submitter clinical testing This sequence change falls in intron 12 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 disease. ClinVar contains an entry for this variant (Variation ID: 432656). 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.

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