Table 1.

Overview of SHANK3 variants analysed in this study.

Variant, domain	Source	Phenotype	Interpretation	Inheritance	Solvent accessibility (%)	ΔΔG (kcal/mol)
D69G SPN	ClinVar	Autism	Unknown significance	De novo	55.77	0.64
Q106P linker	ClinVar	Phelan McDermid syndromea	Unknown significance	Not provided	50.96	1.28
P141A Ank	Ref30	Developmental delay, seizures, autism	Pathogenic	De novo	2.21	1.33
G250C Ank	ClinVar	Not provided	Likely pathogenic	Not provided	24.18	1.73
Q256H Ank	ClinVar	Not provided	Likely pathogenic	Not provided	5.98	0.87
L270M Ank	This study	Learning difficulties; oppositional behavioral disorder; ADHD–like behavior	Unknown significance	Inherited	3.01	1.11
Y272C Ank	ClinVar	Phelan McDermid syndromea	Unknown significance	Not provided	27.8	1.48
Q317R Ank	ClinVar	Not provided	Unknown significance	Not provided	24.48	0.53
T337S Ank	ClinVar	22q13 deletion syndromea	Unknown significance	De novo	52.02	0.11
N52R SPN (no patient mutation	Ref32	–	–	–	0.00	1.06
L68P SPN (already studied before)	Ref39	Autism	Pathogenic	Inherited	5.71	1.47

Solvent accessibility of the residue at this position and free energy changes (ΔΔG values), indicating altered stability, are calculated using PoPMuSiC software. Note that the original publication for the ΔΔG calculation lists a maximum value of ± 4 kcal/mol for destabilising/stabilising variants²⁸.

^aseveral entries in ClinVar are listed as “Phelan-McDermid syndrome” or under the alternative name “22q13 deletion syndrome”, though there is no deletion involved but a missense mutation, as indicated.