ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1849C>T (p.Gln617Ter) (rs201405287)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183759 SCV000280409 likely pathogenic not provided 2011-08-01 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gln617Stop (c.1849 C>T) in PKP2 This variant is novel. Since it creates a new stop codon it is predicted to lead to a truncated protein product or no protein product at all, due to nonsense mediated mRNA decay. The majority of pathogenic PKP2 variants are ones that lead to truncated or aberrant protein product (Van Tintelen et al 2006, den Haan et al 2009). Many nonsense variants in PKP2 have been reported in ARVC cases, including one at the neighboring codon (p.Tyr616Stop), which has been reported multiple times in association with ARVC (van Tintelen et al 2006, Bhuiyan et al 2009, Kapplinger et al 2011). Two recent reports at the Heart Rhythm Society meeting noted more severe phenotypes in individuals with PKP2 nonsense (or other null or truncating) variants compared to those with PKP2 missense variants. A recent analysis of rare variants in desmosomal genes in healthy individuals found several PKP2 missense variants but no nonsense variants (Kapplinger et al 2011). These data further support the pathogenic role of nonsense variants in PKP2. This variant has not been reported in dbSNP (as of June 2011). This variant was not seen in the 427 presumably healthy individuals studied by Kapplinger et al (2011).

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