Submissions for variant NM_000162.5(GCK):c.676G>A (p.Val226Met)

gnomAD frequency: 0.00001  dbSNP: rs148311934

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003155042	SCV004032089	pathogenic	Monogenic diabetes	2023-08-13	reviewed by expert panel	curation	The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID: 10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155042	SCV000052561	pathogenic	Monogenic diabetes	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: GCK c.676G>A (p.Val226Met) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes (gnomAD). c.676G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (example: Velho_1997, Pruhova_2010, Vits_2006). These data indicate that the variant is very likely to be associated with disease. Multiple reports have provided experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Examples: Davis_ 1999 and Miller_1999). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000255932	SCV000322348	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect leading to decreased enzyme activity of the glucokinase protein and may cause a milder phenotype by simultaneously increasing its stability (Davis et al., 1999; Raimondo et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10426385, 25414397, 25306193, 25555642, 10525657, 20337973, 27080136, 27634015, 26897468, 16965331, 17079173, 9049484, 31957151, 32041611, 34108472, 25015100, 21569204, 22101819)
Genetic Services Laboratory, University of Chicago	RCV000029906	SCV000594954	pathogenic	Maturity-onset diabetes of the young type 2	2016-07-19	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255932	SCV000613449	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	This is reported to be a founder variant in the Quebec region of Canada (PMID: 17079173), and is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant resulted in reduced ATP affinity and catalytic activity that could be due to increased protein instability (PMID: 10426385, 10525657, 25015100).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000029906	SCV000891242	likely pathogenic	Maturity-onset diabetes of the young type 2	2016-10-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477021	SCV000894423	pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-09-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825615	SCV000966967	pathogenic	Maturity onset diabetes mellitus in young	2021-08-04	criteria provided, single submitter	clinical testing	The p.Val225Met variant in GCK has been reported in >15 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 8 affected members across 6 families (Velho 1997, Pruhova 2003, Henderson 2007, Delvecchio 2014, Alkorta-Aranburu 2014, Raimondo 2014, Bennett 2015; note that most studies report this variant as p.Val226Met). This variant has also been identified in 0.002% (2/113710) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact to protein function (Davis 1999, Miller 1999, Raimondo 2014). Furthermore, multiple amino acid changes at the same position (p.Val225Glu, p.Val225Leu) have been reported in individuals with MODY, suggesting that changes to this position may not be tolerated. Finally, this variant as been reported as Pathogenic in ClinVar (Variation ID 36243). In summary, the p.Val225Met variant meets criteria to be classified as pathogenic for autosomal dominant MODY based on case observations, segregation studies, low frequency in controls, and functional evidence. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000825615	SCV001656170	pathogenic	Maturity onset diabetes mellitus in young	2017-12-12	criteria provided, single submitter	clinical testing	The c.676G>A (p.Val226Met, rs148311934) variant in exon 6 of GCK is a known pathogenic variant that has been reported in the medical literature (PMID: 17079173). This G to A transition results in the substitution of valine to methionine at amino acid position 226, which results in reduced enzymatic activity of glucokinase (PMID: 25015100).
Centogene AG - the Rare Disease Company	RCV000029906	SCV002059773	pathogenic	Maturity-onset diabetes of the young type 2	2019-04-23	criteria provided, single submitter	clinical testing
Invitae	RCV000255932	SCV002235206	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the GCK protein (p.Val226Met). This variant is present in population databases (rs148311934, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 9049484, 12627330, 17079173, 19790256, 22335469, 25414397, 25555642, 31957151). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36243). 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: 10426385, 10525657). For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV000029906	SCV002562189	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PS4, PP1_Strong, PS3_Moderate, PM2, PP2, PP4_Moderate, PP3, PM1
Ambry Genetics	RCV000825615	SCV002662407	likely pathogenic	Maturity onset diabetes mellitus in young	2020-07-13	criteria provided, single submitter	clinical testing	The p.V226M variant (also known as c.676G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 676. The valine at codon 226 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in multiple individuals with maturity-onset diabetes of the young (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Vits L et al. Clin. Genet., 2006 Oct;70:355-9; Henderson M et al. Mol. Genet. Metab., 2007 Jan;90:87-92; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). In addition, in vitro analyses by multiple groups have suggested that this variant affects enzyme kinetics including reduced activity (Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Davis EA et al. Diabetologia, 1999 Oct;42:1175-86; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.