Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families

Table 3 In-Silico Prediction Analysis of The Detected PCK1 Missense Variants’ Effect on PEPCK-C Function and Structure

		c.574T > C (p.Cys192Arg)	c.1268 C > T (p.Pro423Leu)
Exon		4	8
gnomAD and/or 1000G		Not reported	rs148603002 (Total allele frequency 0.00016)
Mutation taster		Disease-causing
SIFT*	Effect	Damaging
SIFT*	Score	0.01	0
Conservation		Highly conserved
PremPS	ΔΔG (kcal mol-1)**	1.89	0.99
PremPS	Location	Core	Surface
PolyPhen2†	Effect	Probably damaging
PolyPhen2†	Score	0.984	0.998
Hope		The mutant residue introduces a positive charge in a buried residue which can lead to protein folding problems. The mutation will cause a loss of hydrophobic interactions in the core of the protein.	The mutated leucine has a bulky side chain that may affect the enzyme conformation and function
ACMG/AMP classification		Likely pathogenic (PM2, PM3, PP3, PP4, PP5)	Likely pathogenic (PM2, PM3, PP1, PP3, PP4)

* The score ranges from 0 to 1. The amino acid substitution is predicted damaging if the score is < = 0.05, and tolerated if the score is > 0.05
** ΔΔGwt→mut (positive and negative sign corresponds to destabilizing and stabilizing mutations, respectively)
† The score ranges from 0.0 (tolerated) − 1.0 (deleterious)

ISSN: 1750-1172