rs1375656631
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4PM2_SupportingPP1_StrongPP2PP3PM5_SupportingPP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367400584/MONDO:0015967/086
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GCK
NM_000162.5 missense
NM_000162.5 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 7.83
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 Pathogenic. Variant got 14 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
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
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251056Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135790
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461214Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726938
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2022 | Variant summary: GCK c.775G>A (p.Ala259Thr) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251106 control chromosomes. c.775G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes, specifically features of Maturity Onset Diabetes of the Young (MODY2) (example, Hattersley_1998, Matyka_1998, Thomson_2003, Lukasova_208, Capuano_2012, Tatsi_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 12, 2023 | The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting. - |
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 259 of the GCK protein (p.Ala259Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of autosomal dominant maturity onset diabetes of the young (PMID: 9713013, 22761713, 25414397, 26287533, 31638168; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 435302). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 14517956, 25414397, 18271687, 34956103, 29056535, 26875109, 31604004, 9662401, 26287533, 29927023, 9713013, 22761713, 31638168, Sangwoo-2022[Article], 34101350, 35029855) - |
Maturity-onset diabetes of the young type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 11, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
P;P;P;P;.
Vest4
MutPred
0.94
.;Loss of stability (P = 0.0611);.;.;.;
MVP
MPC
1.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at