Submissions for variant NM_000162.5(GCK):c.533G>A (p.Gly178Glu)

dbSNP: rs886039380

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256137	SCV000321713	pathogenic	not provided	2015-07-21	criteria provided, single submitter	clinical testing	The G178E missense variant in the GCK gene has been reported previously in association with MODY (Johansen et al., 2005). Variants in the GCK gene are associated with MODY2, which accounts for approximately 20-50% of MODY cases. Patients with MODY2 typically have mild to moderate fasting hyperglycemia and are often asymptomatic. The majority of patients are managed with diet alone and rarely need pharmacological intervention (Gardner and Tai, 2012; Steck and Winter, 2011). Homozygous or compound heterozygous GCK variants are associated with a more severe form of diabetes mellitus known as permanent neonatal diabetes mellitus (PNDM) (Osbak et al., 2009).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844105	SCV002103383	pathogenic	Maturity-onset diabetes of the young type 2	2022-02-17	criteria provided, single submitter	clinical testing	Variant summary: GCK c.533G>A (p.Gly178Glu) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251062 control chromosomes. c.533G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young type 2 (example, Johansen_2005, Lorini_2009, Pihoker_2013, Bennett_2015, Aykut_2018, Komazec_2019, Saint-Martin_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000256137	SCV003440139	likely pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 178 of the GCK protein (p.Gly178Glu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly178 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 29412391), which suggests that this may be a clinically significant amino acid residue. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 265174). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 15928245, 23771925, 30259503). This variant is not present in population databases (gnomAD no frequency).