rs762263694
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP1_StrongPP2PP3PP4PS2_Moderate
This summary comes from the ClinGen Evidence Repository: 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, LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239720/MONDO:0015967/086
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
GCK
NM_000162.5 missense
NM_000162.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 1.07
Genes affected
GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PS2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GCK | NM_000162.5 | c.106C>T | p.Arg36Trp | missense_variant | 2/10 | ENST00000403799.8 | NP_000153.1 | |
| GCK | NM_033507.3 | c.109C>T | p.Arg37Trp | missense_variant | 2/10 | NP_277042.1 | ||
| GCK | NM_033508.3 | c.103C>T | p.Arg35Trp | missense_variant | 3/11 | NP_277043.1 | ||
| GCK | NM_001354800.1 | c.106C>T | p.Arg36Trp | missense_variant | 2/11 | NP_001341729.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GCK | ENST00000403799.8 | c.106C>T | p.Arg36Trp | missense_variant | 2/10 | 1 | NM_000162.5 | ENSP00000384247 | P1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251440Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461846Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727218
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GnomAD4 genome 0.0000263 AC: 4AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:10
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Maturity-onset diabetes of the young type 2 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Geisinger Clinic, Geisinger Health System | Aug 02, 2022 | PM2, PP3, PP1_Strong, PS4, PM5, PP4, PP2, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | 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). - |
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2024 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 12, 2022 | 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. - |
Maturity onset diabetes mellitus in young Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Jul 20, 2018 | 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. - |
GCK-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 09, 2024 | 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. - |
Monogenic diabetes Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Oct 10, 2023 | 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, - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;D;D;.
Vest4
MutPred
0.87
.;Loss of ubiquitination at K31 (P = 0.0331);.;.;Loss of ubiquitination at K31 (P = 0.0331);
MVP
MPC
2.3
ClinPred
D
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at