Submissions for variant NM_000162.5(GCK):c.184G>A (p.Val62Met)

dbSNP: rs1064793998

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325956	SCV004032100	pathogenic	Monogenic diabetes	2023-08-25	reviewed by expert panel	curation	The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479). In summary, c.184G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_strong, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting.
GeneDx	RCV000481874	SCV000567543	pathogenic	not provided	2023-12-15	criteria provided, single submitter	clinical testing	Published functional studies do not consistently show lowered catalytic activity in standard assays but provide some evidence for decreased thermal stability, or reduced interaction with regulatory proteins (PMID: 17389332, 19187021, 21831042); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21104275, 18322640, 16731834, 17389332, 19187021, 21831042, 19790256, 28726111, 15677479, 37101203, 27271189, 18481947, 18399931, 36257325, 17186219, 16938872, 36880032)
Athena Diagnostics	RCV000481874	SCV000613416	pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with MODY and appears to segregate with disease in at least one family Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15677479, 16938872, 17389332, 19187021)
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000754817	SCV000882467	pathogenic	Maturity-onset diabetes of the young type 2	2018-03-12	criteria provided, single submitter	clinical testing	The c.184G>A variant in codon 62 (exon 3 of the RefSeqGene and of NM_000162.3) of the glucokinase gene, GCK, results in the substitution of Valine to Methionine. Missense mutations in GCK, including ones in this exon, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.184G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.184G>A variant was previously shown to segregate with elevated fasting plasma glucose in three families (15677479, 27271189), A different amino acid substitution at this residue, p.Val62Ala, was shown to segregate with diabetes and impaired glucose tolerance in multiple individuals across four generations in a Norwegian family (9736233, 18399931). Additionally, multiple lines of computational evidence (MutationTaster, FATHMM, MetaSVM, MetalR, Provean, LRT, SIFT, Polyphen, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. Indeed, functional studies have demonstrated impaired enzyme activity of both the p.Val62Met and p.Val62Ala mutant proteins (15677479, 16731834, 17389332, 19187021). ACMG criteria = PP1strong, PS4mod, PS3, PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000754817	SCV001623361	pathogenic	Maturity-onset diabetes of the young type 2	2021-04-21	criteria provided, single submitter	clinical testing	Variant summary: GCK c.184G>A (p.Val62Met) results in a conservative amino acid change located in the Hexokinase, N-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes. c.184G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus and has been shown to segregate with disease in several families (Gloyn_2005, Aloi_2017). These data indicate that the variant is very likely to be associated with disease. The variant has been reported in functional studies to result in lowered catalytic activity/impaired enzyme activity, decreased thermal stability and/or reduced aglucose affinity (Gloyn_2005, Arden_2007, Ralph_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005034013	SCV005668359	pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2024-05-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481874	SCV005835307	pathogenic	not provided	2024-11-27	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 62 of the GCK protein (p.Val62Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 15677479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 419624). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 15677479). This variant disrupts the p.Val62 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9736233, 16731834, 23306198). 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.