Submissions for variant NM_000162.5(GCK):c.751A>G (p.Met251Val)

dbSNP: rs2128820620

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics, Royal Melbourne Hospital	RCV002225198	SCV002503751	pathogenic	Maturity-onset diabetes of the young type 2	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace methionine with valine at codon 251 of the GCK protein, p.(Met251Val). The methionine residue is highly conserved (100 vertebrates, UCSC), and is located in the hexokinase 2 domain. There is a small physicochemical difference between methionine and valine. The variant is absent in a large population cohort (gnomAD v2.1), and has been identified in at least four cases with a clinical diagnosis of maturity-onset diabetes of the young (MODY), co-segregating with diabetes in at least two families (PMID: 20337973, 24804978, 29927023; https://doi.org/10.1093/edrv/36.supp.1). Furthermore, the cases with the variant demonstrate the stable fasting hyperglycaemia, characteristic of MODY type 2 (PMID: 24804978, 29792621). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, a different missense involving this amino acid residue (p.Met251Ile) has been determined to be likely pathogenic (PMID: 14517946). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM2, PM5, PP1, PP3, PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005095775	SCV005835280	pathogenic	not provided	2024-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 251 of the GCK protein (p.Met251Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 12627330, 20337973, 35770790). ClinVar contains an entry for this variant (Variation ID: 1678597). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 35770790). This variant disrupts the p.Met251 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11508276, 22493702; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.