Submissions for variant NM_000162.5(GCK):c.683C>T (p.Thr228Met)

dbSNP: rs80356655

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003883118	SCV004697914	pathogenic	Monogenic diabetes	2024-02-28	reviewed by expert panel	curation	The c.683C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 228 (p.(Thr228Met)) 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 resides in an amino acid that directly binds glucose and ATP, which is defined as critical for the protein's function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In an assay in which the ATPkm was above the MDEP threshold for evaluation of relative activity index (RAI), the Kcat/S0.5 ratio of the Thr228Met variant was 0.0001, which is less than 0.5 of wild type (PS3_Supporting; PMID: 11372010). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 26 unrelated individuals with hyperglycemia (PS4; PMIDs: 21720051, 2721189, 36836406, 36723869, 32741144, 34756319, 11372010, 1502186, 31639168, 24323243, internal lab contributors). At least 2 of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 36723869). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; PMID: 24323243). This variant has been detected in one individual with neonatal diabetes who was found to be homozygous for the c.683C>T variant (PM3_Supporting; PMID: 11372010). In summary, c.683C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PS4, PS2, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting.
GeneDx	RCV000498792	SCV000589594	pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(T228M) nearly eliminates the catalytic activity of the GCK protein (Njolstad et al., 2001; Molnes et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9049484, 28395978, 17573900, 21978167, 17937063, 29056535, 24323243, 31576961, 1502186, 22335469, 14517946, 12955723, 18298419, 21569204, 24735133, 11372010, 8446612, 31638168, 31957151, 32792356, 32741144, 33409956, 34556497, 34746319, 34440516)
Athena Diagnostics Inc	RCV000498792	SCV000613451	pathogenic	not provided	2023-02-24	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 has been identified in multiple unrelated individuals with MODY, has been confirmed to occur de novo in one individual, and appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8446612, 10525657, 21569204)
Invitae	RCV000498792	SCV001589191	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 228 of the GCK protein (p.Thr228Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22335469, 24323243, 31638168). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16134). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 8446612). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000498792	SCV002024232	pathogenic	not provided	2020-07-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000498792	SCV002067325	pathogenic	not provided	2019-06-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.683C>T, in exon 7 that results in an amino acid change, p.Thr228Met. This sequence change has been described in the gnomAD database in the heterozygous state in a single individual (dbSNP rs80356655). This pathogenic sequence change has previously been described in five affected family members with a GCK-MODY phenotype, and was absent from unaffected family members (PMIDs: 1502186). PMID: 11372010, reported this sequence change in the homozygous state in a patient with permanent neonatal diabetes with complete glucokinase deficiency; the parents, who each carried this sequence change, had impaired glucose tolerance or impaired fasting glucose. In vitro functional analysis of the p.Thr228Met variant demonstrated that this variant nearly abolished the catalytic activity of glucokinase (PMID: 11372010). Other pathogenic sequence changes affecting the same amino acid residue (p.Thr228Ala, p.Thr228Arg, p.Thr228Lys) have been described in patients with GCK-MODY (PMIDs: 12955723, 19790256). The p.Thr228Met change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Thr228Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Geisinger Clinic, Geisinger Health System	RCV000020167	SCV002562190	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3
Ambry Genetics	RCV002362586	SCV002666652	pathogenic	Maturity onset diabetes mellitus in young	2016-03-14	criteria provided, single submitter	clinical testing	The p.T228M pathogenic mutation (also known as c.683C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 683. The threonine at codon 228 is replaced by methionine, an amino acid with similar properties. This mutation was first reported in three MODY families; of the family members available for testing, this mutation was identified in all of the affected individuals and in none of the unaffected individuals (Stoffel M, Proc. Natl. Acad. Sci. U.S.A. 1992 Aug; 89(16):7698-702). In another study, a proband with permanent neonatal diabetes was found to be homozygous for this mutation; both mother and father were confirmed heterozygous and had impaired fasting glucose and impaired glucose tolerance, respectively (Nj&oslash;lstad PR, N. Engl. J. Med. 2001 May; 344(21):1588-92). Based on the supporting evidence, p.T228M is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003147295	SCV003835298	pathogenic	Type 2 diabetes mellitus	2022-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147296	SCV003835299	pathogenic	Hyperinsulinism due to glucokinase deficiency	2022-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020167	SCV003835369	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001269032	SCV003836409	pathogenic	Permanent neonatal diabetes mellitus 1	2022-08-23	criteria provided, single submitter	clinical testing
OMIM	RCV000020167	SCV000037786	pathogenic	Maturity-onset diabetes of the young type 2	2001-05-24	no assertion criteria provided	literature only
GeneReviews	RCV000020167	SCV000040495	not provided	Maturity-onset diabetes of the young type 2		no assertion provided	literature only
OMIM	RCV001269032	SCV001448220	pathogenic	Permanent neonatal diabetes mellitus 1	2001-05-24	no assertion criteria provided	literature only