Submissions for variant NM_000162.5(GCK):c.106C>T (p.Arg36Trp)

gnomAD frequency: 0.00003  dbSNP: rs762263694

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003403150	SCV004102863	likely pathogenic	Monogenic diabetes	2023-10-10	reviewed by expert panel	curation	The c.106G>T variant in the glucokinase gene,GCK, causes an amino acid change of arginine to tryptophan at codon 36 (p.(Arg36Trp)) of NM_000162.5. While the Popmax filtering allele frequency is 0.000002920 (European non-Finnish population), which is less than the MDEP cutoff for PM2_Supporting, there are two copies of the variant in the African/African American subpopulation; therefore, PM2_Supporting cannot be applied, and PS4 cannot be applied regardless of the number of cases. 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; PMID: 16965331). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for GCK-MODY (PS2_Moderate; PMID:8168652). This variant segregated with diabetes, with five informative meioses in three families with MODY (PP1_Strong; PMIDs: 17573900, 23433541, 33477506). In summary, c.106C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PS2_Moderate, PP1_Strong,
GeneDx	RCV000497478	SCV000589597	likely pathogenic	not provided	2024-04-19	criteria provided, single submitter	clinical testing	Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 24097065, 28012402, 24430320, 10426385, 14517946, 23433541, 12955723, 21348868, 21521320, 22540858, 16965331, 25555642, 30155490, 22389783, 33477506, 29056535, 38054414, 35218126, 24918535, 17573900, 36257325, 34496959, 16602010, 35592779, 36208030, 36178555, 36208343, 8168652, 36836406, 27935851)
Genetic Services Laboratory, University of Chicago	RCV000503648	SCV000594957	pathogenic	Maturity-onset diabetes of the young type 2	2017-02-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000497478	SCV000613394	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is statistically more frequent in individuals with MODY than in the general population and/or healthy controls. This variant has been identified in at least one individual with clinical features of MODY, including an apparent de novo in one individual. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000788107	SCV000925754	pathogenic	Maturity onset diabetes mellitus in young	2018-07-20	criteria provided, single submitter	clinical testing	The c.106C>T variant (rs762263694) is located in exon 2 of the GCK gene. The C to T transition results in the substitution of arginine for tryptophan at amino acid position 36 of the glucokinase protein. This same variant, as well as a different missense change involving the same amino acid residue (p.Arg36Gln), has been reported in the heterozygous state in several individuals with MODY (PMIDs: 8168652, 25555642, 24097065, 22540858 and others). This is a rare variant in the general population (GnomAD), and the substitution occurs at a position that is highly conserved across species.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497478	SCV002242627	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 36 of the GCK protein (p.Arg36Trp). This variant is present in population databases (rs762263694, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 8168652, 17573900, 21348868, 22493702; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431973). 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. Experimental studies have shown that this missense change does not substantially affect GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV000503648	SCV002562151	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP3, PP1_Strong, PS4, PM5, PP4, PP2, PS3
Ambry Genetics	RCV000788107	SCV002719263	pathogenic	Maturity onset diabetes mellitus in young	2022-08-02	criteria provided, single submitter	clinical testing	The p.R36W pathogenic mutation (also known as c.106C>T), located in coding exon 2 of the GCK gene, results from a C to T substitution at nucleotide position 106. The arginine at codon 36 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with maturity-onset diabetes of the young (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). Functional analysis of this alteration did not show an impact on kinetic activity or thermal stability; however, impact to protein-protein interactions was not assessed (Miller SP et al. Diabetes, 1999 Aug;48:1645-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000503648	SCV005326321	pathogenic	Maturity-onset diabetes of the young type 2		criteria provided, single submitter	clinical testing	The p.Arg36Trp variant substitutes the arginine with tryptophan at amino acid position 36 in the glucokinase protein. This is a recurrent variant that has been reported in the heterozygous state in multiple unrelated individuals with GCK-related MODY (PMID: 35592779 and others). The p.Arg36Trp variant is not common in the general population (observed in 4 of 282,826 alleles; gnomAD v2.1.1). This amino acid position is highly conserved. The p.Arg36Trp variant does not impact kinetics or enzymatic stability of the glucokinase enzyme and is thought to impact protein-protein interactions (PMID: 10426385).
PreventionGenetics, part of Exact Sciences	RCV004751569	SCV005349107	likely pathogenic	GCK-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The GCK c.106C>T variant is predicted to result in the amino acid substitution p.Arg36Trp. This variant has been reported in many individuals with maturity onset diabetes of the young (MODY) (see for example, Table S1, Osbak et al. 2009. PubMed ID: 19790256; Passanisi et al. 2021. PubMed ID: 34496959; Santos Monteiro et al. 2022. PubMed ID: 36208343) and was reported in the de novo state in one of the families (Family F547 at Hager et al. 1994. PubMed ID: 8168652). It was found to segregate with GCK-related disease in at least 3 families (Hager et al. 1994. PubMed ID: 8168652; Giuffrida FM et al 2013. PubMed ID: 23433541; InternalData, PreventionGenetics). A functional study found that this variant had similar kinetic activity and stability compared to wild type; however, this study did not assess potential effects on protein-protein interactions (Miller et al. 1999. PubMed ID: 10426385). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. An alternate nucleotide change, p.Arg36Gln, has been reported in individuals with MODY (Osbak et al. 2009. PubMed ID: 19790256; Marucci et al. 2022. PubMed ID: 36227502). This variant is interpreted as likely pathogenic by the ClinGen Monogenic Diabetes Variant Curation Expert Panel in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/431973/). In summary, this variant is interpreted as likely pathogenic.