Submissions for variant NM_000162.5(GCK):c.871A>G (p.Lys291Glu)

dbSNP: rs193922335

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485201	SCV000565031	likely pathogenic	not provided	2016-09-20	criteria provided, single submitter	clinical testing	The K291E variant that is likely pathogenic has been reported previously in one family with maturity onset of diabetes of the young (MODY) (Osbak et al., 2009). The K291E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). K291E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the hexokinase domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (K291T) and in nearby residues (Q287K/L, Y289H/N/C, E290D, L292P, I293T, G294D, G295C/R/S/D) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485201	SCV002293985	uncertain significance	not provided	2021-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamic acid at codon 291 of the GCK protein (p.Lys291Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 19790256). ClinVar contains an entry for this variant (Variation ID: 418227). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV000485201	SCV003839556	likely pathogenic	not provided	2022-09-03	no assertion criteria provided	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.871A>G, in exon 8 that results in an amino acid change, p.Lys291Glu. The p.Lys291Glu change affects a moderately conserved amino acid residue located in a domain of the GCK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys291Glu substitution. This amino acid change has been described in the literature in one individual with maturity-onset diabetes of the young (MODY) (PMID: 19790256). Additionally, a different pathogenic sequence change affecting the same amino acid residue (p.Lys291Thr) has been described in an individual with GCK-related disorders (PMID: 24725133, 33852230). This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Lys291Glu amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in individuals with GCK-related disorders. This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively. Heterozygous pathogenic variants in GCK are associated with mild fasting hyperglycemia (MODY2) [OMIM# 125851]. Affected individuals rarely show progression of disease or develop microvascular or macrovascular complications typically associated with diabetes. Treatment with oral medications or insulin can result in poorer outcomes as patients have an altered counter-regulatory response to hypoglycemia.