ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2386T>C (p.Cys796Arg) (rs794729098)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183710 SCV000236188 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing The C796R pathogenic variant in the PKP2 gene has been identified in multiple unrelated individuals with ARVD/C and reported to co-segregate with disease phenotype in several families (Gerull et al., 2004; van Tintelen et al., 2006; Campian et al., 2011; Cox et al., 2011; Kapplinger et al., 2011; Kirchner et al., 2012; Noorman et al., 2013; Te Riele et al., 2013). Five unrelated Dutch patients clinically diagnosed with ARVC and harboring C796R were found to share the exact same set of PKP2 haplotype markers, suggesting C796R is a founder mutation in the Dutch population (van Tintelen et al., 2006). Collectively, the C796R variant was absent in over 2,000 control alleles (Gerull et al., 2004; van Tintelen et al., 2006; Campian et al., 2011; Cox et al., 2011). In addition, the C796R pathogenic 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. C796R results in a non-conservative amino acid substitution at a position that is conserved across species. A functional study examining both in vitro and in vivo effects of the C796R variant demonstrated protein instability and degradation via calpain proteases, suggesting haploinsufficiency as the mechanism of disease (Kirchner et al., 2012).In summary, C796R in the PKP2 gene is interpreted as a pathogenic variant.
Invitae RCV000456556 SCV000545219 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 796 of the PKP2 protein (p.Cys796Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) in the Dutch population (PMID: 21636032, 23871674). ClinVar contains an entry for this variant (Variation ID: 201965). Experimental studies have shown that this missense change disrupts the interaction of PKP2 with DSP and leads to PKP2 protein instability (PMID: 22781308, 23863954). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000456556 SCV000743446 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2014-10-08 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000456556 SCV000733155 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing

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