Submissions for variant NM_000162.5(GCK):c.1174C>T (p.Arg392Cys)

dbSNP: rs1167124132

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003318504	SCV004022347	pathogenic	Monogenic diabetes	2023-07-16	reviewed by expert panel	curation	The c.1174C>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Cys at codon 392 (p.(Arg392Cys)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.911 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:29758564 , internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 19 informative meioses in 10 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1174C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4, PS4, PP1_Strong.
Athena Diagnostics	RCV000711758	SCV000842152	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with MODY. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203)
GeneDx	RCV000711758	SCV001816829	likely pathogenic	not provided	2021-05-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24430320, 18382660, 14517946, 18271687, 9662401, 14517956)
Genetic Services Laboratory, University of Chicago	RCV000711758	SCV002070819	likely pathogenic	not provided	2019-01-02	criteria provided, single submitter	clinical testing
Geisinger Clinic, Geisinger Health System	RCV002285406	SCV002562152	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PP2, PP3, PP4, PM2, PS4, PP1_Strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002285406	SCV003934330	likely pathogenic	Maturity-onset diabetes of the young type 2	2023-05-02	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1174C>T (p.Arg392Cys) 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 225042 control chromosomes (gnomAD). c.1174C>T has been reported in the literature in an individual affected with hyperglycemia which cosegregated in pregnancy to the offspring (Hattersley_1998), and in multiple individuals affected with and/or suspected of Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (e.g. Thomson_2003, Katashima_2021, Colclough_2022, Mirshahi_2022). These data indicate that the variant is likely to be associated with disease. However, it has also been observed in at least two individuals without diabetes (Billings_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the same amino acid (Arg392) have been observed in individuals affected with diabetes/MODY (HGMD database), suggesting this amino acid could be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 34789499, 9662401, 34746319, 14517956, 36257325). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either pathogenic (n=1)/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003420270	SCV004107580	likely pathogenic	GCK-related disorder	2023-07-07	criteria provided, single submitter	clinical testing	The GCK c.1174C>T variant is predicted to result in the amino acid substitution p.Arg392Cys. This variant was reported in a family in a low birth weight study (Hattersley et al. 1998. PubMed ID: 9662401). This variant has been reported in multiple individuals with maturity-onset diabetes of the young (Thomson et al. 2003. PubMed ID: 14517956; Katashima et al. 2021. PubMed ID: 34746319; Table S1, Mirshahi et al. 2022. PubMed ID: 36257325; Table S4, Colclough et al. 2022. PubMed ID: 34789499). This variant was also observed in three carriers, one carrier with diabetes and two carriers in the non-diabetes group (Table S1, Billings et al. 2022. PubMed ID: 36208030).This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain/likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/585909/). In summary, this variant is interpreted as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002285406	SCV004175343	pathogenic	Maturity-onset diabetes of the young type 2	2023-07-14	criteria provided, single submitter	clinical testing	The GCK c.1174C>T variant is classified as Pathogenic (PM2_Supporting, PS4, PM5, PP2, PP4_Moderate) The GCK c.1174C>T variant is a single nucleotide change in exon 9/10 of the GCK gene, which is predicted to change the amino acid arginine at position 392 in the protein to cysteine. This variant is absent from population databases (PM2_Supporting). This variant has been reported in multiple unrelated individuals presenting with MODY (PMID: 9662401, 14517956, 34746319, 34789499, 36257325) (PS4). This variant is a novel missense change at an amino acid residue where different missense changes have been seen before (p.Arg392Gly PMID: 34686905, p.Arg392Pro PMID: 24097065, p.Arg392Ser PMID: 18382660) (PM5). This is a missense variant in a constrained gene where missense variants are a common mechanism of disease and benign variation is rare (PP2). The clinical features of this case are highly specific for the GCK gene, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4_Moderate). The variant has been reported in dbSNP (rs1167124132) and has been reported as pathogenic/likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 585909). It is reported in HGMD as disease causing (CM980897).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711758	SCV005835299	likely pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 392 of the GCK protein (p.Arg392Cys). 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 (PMID: 9662401, 14517956, 34746319, 34789499, 36208030, 36257325). ClinVar contains an entry for this variant (Variation ID: 585909). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GCK function (PMID: 37101203). This variant disrupts the p.Arg392 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23624530, 24097065). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002285406	SCV004174088	pathogenic	Maturity-onset diabetes of the young type 2		no assertion criteria provided	clinical testing