The recent worldwide surge in invasive Group A Streptococcal infection (iGAS) has been linked to the emergence of the novel M1UK lineage. Genomic screening of Australian clinical M1UK invasive isolates identified a mutation of A111V in CovR which forms part of the CovRS two-component negative regulatory operon. Under normal circumstances CovR (a transcriptional regulator) dimerises upon phosphorylation by CovS (a histidine kinase) driving transcriptional regulation of up to 15% of the GAS genome. Acquisition of mutations in CovR and CovS (commonly referred to as covRS switching) has been implicated in the upregulation of several bacterial virulence factors in other GAS lineages (e.g. M1T1; a predecessor lineage to M1UK) resulting in a hypervirulent phenotype. While the effect of CovRS switching on GAS virulence is well established, less is known about how different mutations in CovR effect protein function. Our data demonstrate that M1UK containing CovRA111V exhibited a hypervirulent phenotype comparable to M1T1 as reflected by a marked decrease in cysteine protease expression and an increase in expression of haemolytic toxins that promote immune evasion. Molecular dynamics and free energy perturbation simulations suggest that the A111V mutation destabilises the interface between CovR monomers that facilitate dimerisation, which may inhibit CovR transcriptional repression of virulence genes to promote a hypervirulent phenotype. In parallel, exploration of covRS switching frequency of M1UK using an invasive, subcutaneous murine infection model, revealed a ~45% switching rate. This prompted further genomic interrogation of clinical M1UK GAS isolates which identified a range of previously uncharacterised mutations in the covRS operon. Taken together, these data demonstrate evidence of covRS switching in M1UK and provide insight into the structural basis for dysregulation of CovR during infection.