Submission Details

The PRKAG2 gene is associated with PRKAG2-related cardiomyopathy, an autosomal dominant disease characterized by heart-specific glycogenesis, ventricular pre-excitation, supraventricular tachyarrhythmias, and cardiac hypertrophy (Burwinkel et al., 2005, PMID 15877279). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: [Cardiomyopathy, hypertrophic 6] (OMIM: 600858), [Glycogen storage disease of heart, lethal congenital] (OMIM: 261740), [Wolff-Parkinson-White syndrome] (OMIM: 194200). PRKAG2 variants mainly affect the heart, but some studies have reported skeletal myopathy with elevated creatine phosphokinase (Murphy et al., 2005, PMID 15766830; Laforet et al., 2006, PMID 16487706). PRKAG2 encodes the non-catalytic γ subunit of AMPK, a protein kinase that when activated by cellular stress, leads to increased AMP levels and reduced ATP levels. Variants in PRKAG2 are hypothesized to modify the structure of AMPK, altering its affinity for AMP (reviewed in Porto et al., 2016, PMID 26729852). More than 190 individuals comprising at least 13 different variants in PRKAG2 have been reported in the literature, almost all of which are missense variants (Porto et al., 2016, PMID 26729852). 18 variants (17 missense, 1 insertion) that have been reported in 19 probands in 12 publications (PMIDs: 23741347, 11371514, 11827995, 19787389, 16487706, 18403758, 15673802, 28546535, 32259713, 15877279, 31720784, 35588295) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The gene-disease relationship is also supported by expression studies, in vitro functional assays, and model systems (PMIDs: 11112354, 28009297, 17667862, 15877279, 28917552, 28917552, 16339829, 15611370). In summary, there is definitive evidence supporting the relationship between PRKAG2 and autosomal dominant PRKAG2-related cardiomyopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on April 4, 2017. It was reevaluated by the Hereditary Cardiovascular Disease GCEP on June 14, 2022 (SOP Version 9). As a result of this reevaluation, the classification did not change.