Submissions for variant NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

dbSNP: rs193922340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001805831	SCV005687804	pathogenic	Monogenic diabetes	2025-01-16	reviewed by expert panel	curation	The c.952G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 318 (p.(Gly318Arg)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthemore, this variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491, and 36208343). This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325). Additionally, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID: 31416898). In summary, c.952G>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 8/11/23): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting.
Athena Diagnostics	RCV000711789	SCV000842186	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced affinity of the enzyme to glucose (PMID: 28842611).
GeneDx	RCV000711789	SCV002031111	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 21348868, 33852230, 26641800, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 31416898, 30245511, 23433541, 36257325, 34440516, 34556497, 35472491, 36208343, 35737141, 22332836)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805831	SCV002051328	pathogenic	Monogenic diabetes	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: GCK c.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247788 control chromosomes. c.952G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes presenting as MODY2 (Maturity Onset Diabetes of the Young) (example, Thomson_2003, Pruhova_2003, Feigeriova_2006, Dustakova_2012, Valentinova_2012, Gal_2021). 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. Two 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711789	SCV002235363	pathogenic	not provided	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). 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 (MODY) (PMID: 12627330, 22493702, 28663157, 29207974). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585929). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000711789	SCV002502879	likely pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001805831	SCV002761528	likely pathogenic	Monogenic diabetes	2021-06-18	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Medical University of Lodz	RCV004797865	SCV005419227	pathogenic	Maturity-onset diabetes of the young type 2	2024-12-03	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813133	SCV005438191	pathogenic	Pancytopenia-developmental delay syndrome	2024-12-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000711789	SCV005910138	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	GCK: PS4, PM2, PM6, PP1, PP3
PreventionGenetics, part of Exact Sciences	RCV004751675	SCV005361958	pathogenic	GCK-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The GCK c.952G>A variant is predicted to result in the amino acid substitution p.Gly318Arg. This variant is predicted to alter splicing by strengthening a cryptic splice site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751; Alamut Visual v1.6.1). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported in individuals with maturity-onset diabetes of the young and noted to segregate with disease in several families (Pruhova et al. 2003. PubMed ID: 12627330; Dusatkova et al. 2012. PubMed ID: 22332836; Wędrychowicz et al. 2017. PubMed ID: 28663157). In addition, it has been reported as a founder variant in individuals of Czech ancestry (Dusatkova et al. 2012. PubMed ID: 22332836). A different missense variant affecting the same amino acid (p.Glu318Ala), has been reported in an individual with maturity-onset diabetes of the young (Gloyn. 2003. PubMed ID: 14517946). This variant is interpreted as pathogenic.