Submissions for variant NM_000162.5(GCK):c.1148C>T (p.Ser383Leu)

dbSNP: rs777870079

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003226260	SCV004697909	pathogenic	Monogenic diabetes	2024-02-28	reviewed by expert panel	curation	The c.1148C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to leucine at codon 383 (p. (Ser383Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.831 which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.20, which is below the MDEP cutoff (<0.5) (Matschinsky FM, Magnuson MA (eds): Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front. Diabetes. Basel, Karger, 2004, vol 16, pp 92-109). This variant has been identified in at least 53 unrelated individuals with hyperglycemia and segregated with the phenotype, with 30 informative meioses in 49 families (PS4, PP1_Strong; PMID: 28555465, 30663027, 34462253, 34746319, internal lab contributors). At least of of these patients had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative GAD-65 (PP4_Moderate; PMID: 28555465). In summary, c.1148C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PS4, PP4_Moderate, PP2, PP1_Strong, PM2_Supporting
Kangwon National University Hospital	RCV000225001	SCV000280569	likely pathogenic	Maturity-onset diabetes of the young type 2	2017-07-17	criteria provided, single submitter	clinical testing	Glucokinase-maturityonset diabetes of the young (GCKMODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. Because people with GCK-MODY do not develop significant microvascular complications, treatment is not recommended except pregnancy. Glucose-lowering therapy is ineffective in people with GCK-MODY.
GeneDx	RCV000420976	SCV000516034	likely pathogenic	not provided	2021-05-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 12050210, 32533152, 19790256, 14517946, 24918535, 17573900, 11942313, 28555465, 30663027, 21348868, 20337973, 16963153, 16602010, 15841481, 32375122, 31216263, 33242514, 32041611)
Genetic Services Laboratory, University of Chicago	RCV000225001	SCV000594950	likely pathogenic	Maturity-onset diabetes of the young type 2	2016-09-09	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000420976	SCV000613403	likely pathogenic	not provided	2016-12-21	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000225001	SCV002556571	likely pathogenic	Maturity-onset diabetes of the young type 2	2021-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000420976	SCV003439540	pathogenic	not provided	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 383 of the GCK protein (p.Ser383Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of GCK-related conditions (PMID: 12050210, 15841481, 17573900, 20337973, 22525692, 24918535, 28555465, 30447144, 30663027, 31216263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236014). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226260	SCV003922549	pathogenic	Monogenic diabetes	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: GCK NM_000162.3:c.1148C>T (p.Ser383Leu) results in a non-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 was absent in 234324 control chromosomes. c.1148C>T has been reported in the literature in multiple individuals affected with features of Monogenic Diabetes (Maturity Onset Diabetes Of The Young 2) (example, PMID: 12050210, 28555465, 20337973, 36208343). 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. Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.