Submissions for variant NM_000162.5(GCK):c.127C>T (p.Arg43Cys)

dbSNP: rs1486280029

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325972	SCV004032096	pathogenic	Monogenic diabetes	2023-08-13	reviewed by expert panel	curation	The c.127C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 43 (p.(Arg43Cys)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, established functional studies demonstrated the p.Arg43Cys protein has a relative activity index (RAI) < 0.5, indicating that this variant impacts protein function (PS3_Moderate; PMID: 25015100). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least eight unrelated individuals with hyperglycemia/diabetes (PS4; PMIDs: 30592380, 21348868, PMID 23771172, 25015100). One of these individuals was homozygous for c.127C>T and had permanent neonatal diabetes mellitus (PNDM) and negative testing for ABCC8, KCNJ11, INS and EIF2AK3 (PP4; PMID 25015100). This variant also segregated with diabetes/hyperglycemia, with 5 informative meioses in one family (PP1_Strong; PMID 21348868). Another missense variant, c.128G>A (p.Arg43His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg43Cys has a greater Grantham distance (PM5). Taken together, this evidence supports the classification of this variant 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, PS4, PM5, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate.
Athena Diagnostics	RCV000711761	SCV000842155	pathogenic	not provided	2020-05-11	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Found in multiple individuals with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family.
Geisinger Clinic, Geisinger Health System	RCV002285407	SCV002562156	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PS4, PP1_Strong, PP2, PP3, PP4, PM2, PS3_Moderate, PM5
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711761	SCV004295191	pathogenic	not provided	2024-07-19	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 43 of the GCK protein (p.Arg43Cys). 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: 19790256, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). 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%. Experimental studies have shown that this missense change affects GCK function (PMID: 30592380). This variant disrupts the p.Arg43 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11942313, 22493702, 22611063, 28726111, 30155490, 30245511, 31638168, 33046911, 34108472; Invitae). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711761	SCV004565214	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	The GCK c c.127C>T; p.Arg43Cys variant (rs1486280029) is reported in the literature in multiple individuals and families affected with MODY and neonatal diabetes (Ellard 2013, Marucci 2023, Osbak 2009, Wang 2019). This variant is also reported in ClinVar (Variation ID: 585911). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Gly, Ser, His, Pro) have been reported in individuals with MODY with most of them demonstrating pathogenicity (Osbak 2009). Computational analyses predict that this variant is neutral (REVEL: 0.924). Based on available information, this variant is considered to be pathogenic. References: Ellard S et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013 Sep;56(9):1958-63. PMID: 23771172. Marucci A et al. MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience. Acta Diabetol. 2023 Jan;60(1):131-135. PMID: 36227502. Osbak KK et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009 Nov;30(11):1512-26. PMID: 19790256. Wang Z et al. Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. J Diabetes Investig. 2019 Jul;10(4):963-971. PMID: 30592380.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003325972	SCV004813475	pathogenic	Monogenic diabetes	2024-02-21	criteria provided, single submitter	clinical testing	Variant summary: GCK c.127C>T (p.Arg43Cys) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) 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 251444 control chromosomes. c.127C>T has been reported in the literature in multiple heterozygous individuals affected with Monogenic Diabetes (e.g. Boroweic_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing decreased catalytic activity in vitro (e.g. Wang_2019). The most pronounced variant effect results in 30%-50% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 21348868, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004819230	SCV005440569	pathogenic	Permanent neonatal diabetes mellitus 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PP1_Strong+PP4+PM5+PP3
Fulgent Genetics, Fulgent Genetics	RCV005046971	SCV005668363	pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2024-05-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751674	SCV005341337	pathogenic	GCK-related disorder	2024-03-04	no assertion criteria provided	clinical testing	The GCK c.127C>T variant is predicted to result in the amino acid substitution p.Arg43Cys. This variant has been reported in heterozygous state in multiple individuals with mature onset diabetes of the young (MODY) (Table S1, Osbak et al. 2009. PubMed ID: 19790256; Wang et al. 2019. PubMed ID: 30592380) and in one family was reported to segregate with MODY (Borowiec et al. 2012. PubMed ID: 21348868). Additionally, this variant has been reported in the homozygous state in individuals with neonatal diabetes (Raimondo et al. 2014. PubMed ID: 25015100). In vitro functional studies found this variant results in decreased catalytic activity and decrease stability at higher temperatures (Wang et al. 2019. PubMed ID: 30592380). Alternate missense variants affecting the same amino acid (p.Arg43Ser, p.Arg43Gly, p.Arg43His, p.Arg43Pro) have been reported as pathogenic (Table S1, Osbak et al. 2009. PubMed ID: 19790256). This variant has not been reported in a large population database and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/585911/). This variant is interpreted as pathogenic.