The titin gene (TTN), with its 364 exons, encodes the largest human protein. It gives rise to a dizzying array of alternatively spliced isoforms differentially expressed in various skeletal muscles, heart, and in development. Titin is not only the main spring element of the sarcomere, extending all the way from the Z-disc to the M-band, but it is also a stretch sensor and is involved in atrophy and other signaling pathways while interacting with a large and growing number of proteins, exerting many control and regulatory functions in muscles.1 No transcriptional unit exemplifies the unique diagnostic challenges posed by such a large and complex gene better than TTN. Until recently, the biggest challenge was to simply fully sequence TTN. Now, next-generation sequencing panels as well as whole-exome platforms have made TTN accessible to full-length testing on a routine basis. This development has rapidly increased diagnostic yields while amplifying the challenges posed by an increasingly large number of sequence variants of uncertain significance resulting from this high-throughput sequencing. These findings highlight the urgent need to confidently clarify the relevance of these variants. Savarese et al2 do an admirable job of illustrating and addressing these challenges.