rs1375656631

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

Scores

14
3
2

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 7.83
Variant links:
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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCKNM_000162.5 linkc.775G>A p.Ala259Thr missense_variant Exon 7 of 10 ENST00000403799.8 NP_000153.1 P35557-1Q53Y25

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkc.775G>A p.Ala259Thr missense_variant Exon 7 of 10 1 NM_000162.5 ENSP00000384247.3 P35557-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251056
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461214
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726938
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:2
Aug 18, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 12, 2023
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

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
Jun 23, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jan 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Maturity-onset diabetes of the young type 2 Pathogenic:1
Jan 11, 2017
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
.;D;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;.;D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;H;.;.;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.5
.;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
.;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
0.90
P;P;P;P;.
Vest4
0.94
MutPred
0.94
.;Loss of stability (P = 0.0611);.;.;.;
MVP
0.98
MPC
1.8
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.92
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1375656631; hg19: chr7-44187337; COSMIC: COSV60787622; COSMIC: COSV60787622; API