The determination of the mutational status in the immunoglobulin variable region is an established prognostic biomarker for chronic lymphocytic leukemia (CLL). The length and inner variability of the variable, diversity, and joining (VDJ) rearranged sequences compromises B-cell clones characterization using next-generation sequencing (NGS), and a standardization is needed to adapt the procedure to the current clinical guidelines. We have developed a complete strategy for sequencing the variable domain of the immunoglobulin heavy chain gene (IGH) locus with a simple, low-cost, and efficient method that allows sequencing using shorter reads (MiSeq 150 × 2) and thus faster obtention of results. Clonality and mutational status determination are performed within the same analysis pipeline. We tested and validated the method using 319 CLL patients previously diagnosed and IGH locus characterized using Sanger sequencing, and 47 healthy donor samples. The analysis method follows a clone-centered consensus sequence strategy, to identify B-cell clones and establish a clonal threshold specific for each patient clonality profile, overcoming limitations of Sanger sequencing which is the gold standard used for immunoglobulin heavy variable (IGHV) mutational status determination.