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Traditionally, lattice QCD computations of generalized parton distributions (GPDs) have been carried out in a symmetric frame, where the transferred momentum is symmetrically distributed between the incoming and outgoing hadrons. However, such frames are inconvenient since they require a separate calculation for each value of the momentum transfer, increasing significantly the computational cost. In this work, by focusing on the quasi-distribution approach, we lay the foundation for faster and more effective lattice QCD calculations of GPDs exploiting asymmetric frames, with freedom in the transferred momentum distribution. An important ingredient of our approach is the Lorentz covariant parameterization of the matrix elements in terms of Lorentz-invariant amplitudes, which allows one to relate matrix elements in different frames. We also use this amplitude approach to propose a new definition of quasi-GPDs that is frame-independent and, more importantly, may lead to smaller power corrections in the matching relations to the light-cone GPDs. We demonstrate the efficacy of the formalism through numerical calculations using one ensemble of $N_f$=2+1+1 twisted mass fermions with a clover improvement. The value of the light-quark masses lead to a pion mass of about 260 MeV. Concentrating on the proton, and limiting ourselves to a vanishing longitudinal momentum transfer to the target, we extract the invariant amplitudes from matrix element calculations in both the symmetric and asymmetric frame, and obtain results for the twist-2 light-cone GPDs for unpolarized quarks, that is, $H$ and $E$.