Table 2.

Genetic feature of YWHAG mutations.

cDNA change (NM_012479.3)	Protein change (NP_036611.2)	Phenotype	MAF	Inheritance	Damaging prediction‡	ΔΔGAffinity (kcal/mol)§	PIS	ACMG (scoring)
c.124C>T†	p.Arg42Ter	FS+, myoclonic seizures	0	Family	–	–	–	P (PVS1 + PM2 + PP1)
c.373A>G†	p.Lys125Glu	FS+, myoclonic seizures	0	de novo	18	−0.635	No	LP (PS2 + PM2 + PP3)
c.44A>C	p.Glu15Ala	Epileptic encephalopathy	0	de novo	15	−0.620	Yesa	LP (PS2 + PM2 + PP3)
c.169C>G	p.Arg57Gly	Epileptic encephalopathy	0	de novo	19	−0.517	Yesb	LP (PS2 + PM2 + PP3)
c.169C>T	p.Arg57Cys	Epileptic encephalopathy	0	de novo	19	−0.360	Yesb	LP (PS2 + PM2 + PP3)
c.387C>G	p.Asp129Glu	Epileptic encephalopathy	0	de novo	19	−0.969	Yesb	LP (PS2 + PM2 + PP3)
c.394C>T	p.Arg132Cys	Epileptic encephalopathy	0	de novo	18	−1.288	Yesb	LP (PS2 + PM2 + PP3)
c.398A>C	p.Tyr133Ser	Developmental delay, epileptic encephalopathy	0	de novo	19	−0.611	Yesb	LP (PS2 + PM2 + PP3)
c.529C>A	p.Leu177Ile	Epileptic encephalopathy	0	de novo	18	−1.193	Yesc	LP (PS2 + PM2 + PP3)
c.532A>G	p.Asn178Asp	Epileptic encephalopathy	0	de novo	18	−0.010	Yesb	LP (PS2 + PM2 + PP3)
c.148A>C	p.Lys50Gln	Autism spectrum disorder	0	de novo	18	−0.534	No	LP (PS2 + PM2 + PP3)

ACMG, American College of Medical Genetics and Genomics (P, pathogenic; LP, likely pathogenic); FS+, febrile seizure plus; MAF, minor allele frequency from gnomAD; PIS, primary interaction sites; PVS1, Predicted null variant in a gene where loss-of-function is a known mechanism of disease; PS2, De novo in a patient with the disease and no family history; PM1, Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation; PM2, Absent in population databases; PP1, Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; PP3, Multiple lines of computational evidence support a deleterious effect on the gene/gene product.

^†Variant identified in this study.

^‡Variant predicted to be damaging out of 21 prediction tools.

^§Protein-protein affinity change upon variant indicated by free energy change.

^aA crucial site involved in 14-3-3γ dimerization.

^bA part of conserved triads (Arg132-Arg57-Tyr133 and Asp129-Asn178-Asn229) for fixing the orientation of the phosphopeptides.

^cA part of conserved hydrophobic patch (Leu-177-Leu-221-Ile-222) complements the hydrophobic character of the peptide.