ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2419del (p.Thr807fs)

dbSNP: rs727504786
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156104 SCV000205817 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-08 criteria provided, single submitter clinical testing The p.Thr851fsExtX50 variant in PKP2 has not been previously reported in any oth er families with cardiomyopathy or in large population studies. This variant is predicted to cause a frameshift at amino acid 851 which alters the terminal 30 a mino acids and the stop codon such that an additional 50 amino acids are generat ed before introducing a new stop codon. Heterozygous loss of PKP2 function is an established disease mechanism for ARVC; however it is unclear how the p.Thr851f sExtX50 variant would impact the protein function. Of note, 4 other variants hav ing a similar impact to the protein (p.Ser837fsExtX50, p.Leu847fsExtX50, p.Glu85 2fsExtX50, p.Lys859fsExtX50) have been described in >15 individuals with ARVC (G erull 2004, Antoniades 2006, Dalal 2006, Asimaki 2009, Dalal 2009, Fressart 2010 , Den Haan 2009, Watkins 2009, Qiu 2009, Xu 2010, Barahona-Dussault 2010, Tan, 2 010, Cox 2011, Baskin 2013, Alcalde 2014), suggesting that PKP2 protein extensio n variants are disease-causing. In summary, although additional studies are requ ired to fully establish its clinical significance, the p.Thr851fsExtX50 variant is likely pathogenic.

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