ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.253_256del (p.Glu85fs) (rs786204388)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412778 SCV000490723 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The c.253_256delGAGT pathogenic variant in the PKP2 gene has been reported previously in at least 2 individuals with ARVC and was absent in 1,200 healthy control alleles collectively (Fressart V et al., 2010; Bao J et al., 2013). Additionally, the c.253_256delGAGT variant has been reported as a pathogenic variant by one other clinical laboratory in the ClinVar database (Landrum M et al., 2014). Furthermore, the c.253_256delGAGT deletion 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. This variant causes a shift in reading frame starting at codon Glutamic acid 85, changing it to a Methionine, and creating a premature stop codon at position 26 of the new reading frame, denoted p.Glu85MetfsX26. This deletion is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson P et al., 2014). In summary, c.253_256delGAGT in the PKP2 gene is interpreted as a pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000999610 SCV001156314 likely pathogenic Sudden unexplained death 2018-02-09 criteria provided, single submitter research PKP2 Glu85Metfs*26 has been previously reported in 1 ARVC patient (Fressart V, et al., 2010). We identified this variant in a case of sudden unexplained death in a young male. Genetic testing in this individual also identified two other variants (CASQ2 Phe189Leu & NEBL Gln682Ter). The variant is absent from the Genome Aggregation Database ( on rarity in the general population and because loss of function variants in PKP2 is an established mechanism of disease, we classify PKP2 Glu85Metfs*26 as "likely pathogenic".

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