Table 3.

Classification of LD-causing EPM2A missense mutations based on biochemical and clinical data

Functional class	Structural group	Mutations	General effects	Predicted pathogenicity
Class I	CBM	W32G K87T	Severely impaired carbohydrate binding and phosphatase activity; decreased PTG interaction	Severe
Class IIa	CBM	(F5S) V7A E28K F84L (Y86D) F88L R91P (R108C)	Destabilized and decoupled CBM and DSP domain; mild or moderate effects on phosphatase activity; severely impaired PTG and malin interaction.	Severe
Class IIb	CBM-DSP interface	E56K Y294N P301L
Class III	DSP domain	N148Y N163D∗ (T187A) A188G L310W G279S∗ G279C∗	Destabilized; variable effects on phosphatase activity; impaired malin and PTG interaction.	Variable
Class IV	DSP domain (V-loop)	E210K P211L∗ E224I	Slightly destabilized; slight decrease in activity; slight or no decrease in malin and PTG interaction.	Moderate
Class V	Dimer interface	F321C∗∗	Destabilized; mild effects on phosphatase activity; impaired malin interaction; loss of dimerization and preferential binding to long oligosaccharides	Mild
Unknown	Various	S25P K140N G240S P246A	Mild or no effect on stability or activity. S25P displays no interaction with malin or PTG.	Unknown

Asterisk(s) indicates this mutation has been associated with a milder phenotype, either in the compound heterozygous (∗) or homozygous (∗∗) state. Mutants in parentheses are likely classifications but were not fully characterized due to their insolubility in E. coli. N163D was previously characterized (Garcia-Gimeno et al., 2018).