Background: Myotonic dystrophy type 1 (DM1) is caused by expansion of an unstable CTG repeat in the DMPK gene. The average number of repeats reported in routine diagnostics is broadly correlated with disease severity, but with limited predictive value and is not provided to patients in genetic counselling. OPTIMISTIC is a large international randomised trial of the efficacy of personalised cognitive behavioural therapy and graded exercise in DM1. Objective: Evaluate the genetic basis of symptomatic diversity in 250 adult, ambulant DM1 patients recruited through OPTIMISTIC. Methods: We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed-PCR to test for the presence of variant repeats. Results: We confirmed disease severity is driven by progenitor allele length, is further modified by sex and that patients with faster expansion rate develop symptoms earlier than predicted. We quantified the critical role of variant repeats in delaying age at onset by approximately 13.2 years (95% CI = 5.7 to 20.7, two-tailed t-test, t = 3.7, p = 0.0019). Conclusions: Careful characterisation of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining the basis of treatment response and stratification in DM1 trials. We suggest to re-evaluate the recommended diagnostic criteria for DM1 and the potential value of reporting more informative prognostic information to families.