Submissions for variant NM_000162.5(GCK):c.766G>A (p.Glu256Lys)

dbSNP: rs769268803

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255753	SCV000321715	pathogenic	not provided	2024-07-19	criteria provided, single submitter	clinical testing	Not observed at 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25306193, 23778137, 27634015, 28331372, 18397317, 36257325, 25555642, 34789499, 22101819, 15016359, 8446612, 23476789, 31957151, 20337973, 27913849, 23624530, 26123671, 17573900)
Athena Diagnostics	RCV000255753	SCV000613455	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with MODY. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 18397317.
Fulgent Genetics, Fulgent Genetics	RCV000763583	SCV000894422	pathogenic	Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255753	SCV002245931	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the GCK protein (p.Glu256Lys). This variant is present in population databases (rs769268803, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 17573900, 27634015, 28331372, 31957151). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265175). 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 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: 8446612). For these reasons, this variant has been classified as Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000255753	SCV002525645	pathogenic	not provided		criteria provided, single submitter	clinical testing	The c.766G>A variant in exon 7 of the GCK gene substitutes the glutamic acid with lysine at amino acid position 256 of the glucokinase protein. This is a recurrent pathogenic variant that has been reported in the heterozygous state in several individuals with MODY. It is not a common variant in the general population (observed in 1 of 251,142 alleles; GnomAD v2.1). The p.Glu256Lys variant falls within the glucose binding site of GCK and has been experimentally demonstrated to cause a loss of catalytic activity. PMIDs: 25555642, 27634015, 28331372, 23476789, 8446612, NBK500456, 30225972, 21844708, 23771172
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493556	SCV004244361	pathogenic	Maturity-onset diabetes of the young type 2	2024-01-22	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM5,PM2_SUP,PP1,PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255753	SCV004562624	pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	The GCK c.766G>A; p.Glu256Lys variant (rs769268803) is reported in the literature in multiple patients with maturity-onset diabetes of the young, type II (MODY2) and non-insulin-dependent diabetes (NIDDM), although no clear co-segregation is shown (Brahm 2016, Emelyanov 2017, Mirshahi 2022, Xu 2020). This variant is also reported in ClinVar (Variation ID: 265175) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Multiple lines of conformational and functional studies showed that this variant is part of the critical glucose binding domain (Yellapu 2013) and has profound impact on GCK catalytic activity ex vivo (Gidh-Jain 1993). Different amino acid substitutions at this residue (p.Glu256Ala, p.Glu256Asp, and p.Glu256Gly) have also been reported in patients with MODY2 and are considered to be disease-causing (Santana 2017, Garin 2008, Zmyslowska 2022). The glutamic acid at codon 256 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.977). Based on available information, the p.Glu256Lys variant is considered to be pathogenic. References: Brahm AJ et al. Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. Can J Diabetes. 2016 Dec;40(6):555-560. PMID: 27634015. Garin I, et al. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf). 2008 Jun;68(6):873-8. PMID: 18248649. Gidh-Jain M, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID: 8446612. Emelyanov AO et al. A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance. Int Med Case Rep J. 2017 Mar 7;10:77-80. PMID: 28331372. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Santana LS et al. Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. Clin Genet. 2017 Oct;92(4):388-396. PMID: 28170077. Xu A et al. Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. Pediatr Diabetes. 2020 May;21(3):431-440. PMID: 31957151. Yellapu NK et al. Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study. Biotechnol Res Int. 2013;2013:264793. PMID: 23476789. Zmyslowska A et al. Next- generation sequencing is an effective method for diagnosing patients with different forms of monogenic diabetes. Diabetes Res Clin Pract. 2022 Jan;183:109154. PMID: 34826540.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987481	SCV004804230	pathogenic	Monogenic diabetes	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: GCK c.766G>A (p.Glu256Lys) 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 4e-06 in 251142 control chromosomes (gnomAD). c.766G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (examples: Wajngot_1994, Estalella_2007 Brahm_2016, Emelyanov_2017, Colclough_2022) and at-least has been reported as a de novo occurrence (Emelyanov_2017). At least one publication reports experimental evidence that this variant impairs normal protein activity (Gidh-Jain_1993). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8446612, 17573900, 28331372, 27634015, 34789499, 7958490). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV004547644	SCV005043520	pathogenic	Maturity onset diabetes mellitus in young	2019-09-12	criteria provided, single submitter	clinical testing	The p.E256K pathogenic mutation (also known as c.766G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 766. The glutamic acid at codon 256 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in multiple individuals and families with maturity-onset diabetes of the young (MODY) (Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Irgens HU et al. Diabetologia, 2013 Jul;56:1512-9). Based on structural analysis, this variant is anticipated to disrupt glucose binding, resulting in reduced activity (Pilkis SJ et al. J. Biol. Chem., 1994 Sep;269:21925-8; Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Yellapu NK et al. Biotechnol Res Int, 2013 Feb;2013:264793). Functional studies have illustrated this, by showing that E256K mutant protein has significantly reduced enzymatic activity (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Molnes J et al. FEBS J., 2008 May;275:2467-81). In addition, another alteration at the same codon, p.E256D, has been reported to cause MODY (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). Based on the supporting evidence, p.E256K is interpreted as a disease-causing mutation.