rs80356655
Variant summary
Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PP4_ModeratePM2_SupportingPP2PP3PM1PS4PS2PM3_SupportingPP1_StrongPS3_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA260620/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 21 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250034Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135572
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3AN: 1461004Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726816
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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) -
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) -
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). -
The GCK c.683C>T; p.Thr228Met variant (rs80356655, ClinVar Variation ID: 16134) is reported in the literature in numerous individuals affected with maturity-onset diabetes of the young (MODY) and non-insulin-dependent diabetes (NIDDM; Breidbart 2021, Campos Franco 2022, Glotov 2019, Katashima 2021, Lin 2020, Stoffel 1992) and in one homozygous individual with neonatal diabetes (Niolstad 2001). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show decreased enzymatic activity (Gidh-Jain 1993, Njolstad 2001). Computational analyses predict that this variant is deleterious (REVEL: 0.966). Based on available information, this variant is considered to be pathogenic. References: Breidbart E et al. Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry. J Pediatr Endocrinol Metab. 2021 Apr 13;34(5):633-638. PMID: 33852230. Campos Franco P et al. Clinical and genetic characterization and long-term evaluation of individuals with maturity-onset diabetes of the young (MODY): The journey towards appropriate treatment. Diabetes Res Clin Pract. 2022 May;187:109875. PMID: 35472491. Gidh-Jain M et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID: 8446612. Glotov OS et al. Whole-exome sequencing in Russian children with non-type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY-related and unrelated genes. Mol Med Rep. 2019 Dec;20(6):4905-4914. PMID: 31638168. Katashima R et al. Identification of Novel GCK and HNF4a Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age. J Diabetes Res. 2021 Oct 29;2021:7216339. PMID: 34746319. Lin Y et al. Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age. BMJ Open Diabetes Res Care. 2020 Aug;8(1):e001345. PMID: 32792356. Njolstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001 May 24;344(21):1588-92. PMID: 11372010. Stoffel M et al. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7698-702. PMID: 1502186. -
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). 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) has been performed 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. -
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Maturity-onset diabetes of the young type 2 Pathogenic:3Other:1
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PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 -
Permanent neonatal diabetes mellitus 1 Pathogenic:2
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Maturity onset diabetes mellitus in young Pathogenic:2
The p.Thr227Met variant in GCK has been previously identified in at least 8 individuals with maturity-onset diabetes of the young (MODY), was de novo in at least one individual, and segregated with disease in affect relatives (Estalella 2007 PMID: 17573900; Stern 2007 PMID: 17937063; Delvecchio 2013 PMID: 22335469; Stanik 2014 PMID: 24323243; Costantini 2015 PMID: 24735133; Aykut 2018 PMID: 29056535; Glotov 2019 PMID: 31638168; Xu 2020 PMID: 31957151). In addition, this variant has been identified in individividuals with type 2 diabetes, gestational diabetes, and in the homozygous state in neonatal diabetes (Kousta 2001 PMID: 11553210; Njølstad 2001 PMID:11372010; Yokota 2011 PMID: 21720051). This variant has been identified in 0.003% (1/34570) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 16134). Functional studies provide evidence that this variant impacts protein function (Molnes 2011 PMID: 21569204; Njølstad 2001 PMID:11372010; Gidh-Jain 1993 PMID: 8446612; Stoffel 1992 PMID: 1502186), and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant (p.Thr228Ala) has been identified in individuals with monogenic diabetes. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4_Moderate; PM2; PM5_Supporting; PS2; PS3_Supporting; PP3. -
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 (Njølstad 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. -
Type 2 diabetes mellitus Pathogenic:1
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GCK-related disorder Pathogenic:1
The GCK c.683C>T variant is predicted to result in the amino acid substitution p.Thr228Met. This variant has been repeatedly reported to be pathogenic for MODY (see for example Stoffel et al. 1992. PubMed ID: 1502186; Gidh-Jain et al. 1993. PubMed ID: 8446612; Stanik. 2014. PubMed ID: 24323243; Costantini et al. 2015. PubMed ID: 24735133; Glotov et al. 2019. PubMed ID: 31638168). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -
Monogenic diabetes Pathogenic:1
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. -
Hyperinsulinism due to glucokinase deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at