ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1378+1G>C (rs397516994)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038161 SCV000061827 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2010-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000183806 SCV000236287 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The c.1378+1 G>C variant in the PKP2 gene has been published previously in at least three unrelated individuals meeting clinical task force criteria for ARVC, as well as one carrier patient with sub-clinical features elicited by exercise testing (Fressart et al., 2010; Medeiros-Domingo et al., 2016; Perrin et al., 2013). Furthermore, c.1378+1 G>C 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. Splice site algorithms predict this variant destroys the canonical splice donor site in intron 5 while maintaining the adjacent exon 5 in-frame. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Finally, although this variant has also been reported in several other individuals referred for cardiomyopathy testing at GeneDx, familial segregation information is limited or absent, and at least one individual harbored a second variant of uncertain significance in a different gene. Therefore, this variant is a strong candidate for a pathogenic variant, however, the possibility that it is a benign variant cannot be excluded.
Ambry Genetics RCV000244525 SCV000320057 pathogenic Cardiovascular phenotype 2018-08-14 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Blueprint Genetics RCV000038161 SCV000207152 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-04-25 no assertion criteria provided clinical testing

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