rs587780343

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP1_StrongPP4_ModeratePP2PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1112G>T variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to phenylalanine at codon 371 (p.(Cys371Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.931, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was hyperglycemia (PS4; PMID 24735133, internal lab contributors). This variant segregated with hyperglycemia with 12 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as either OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PP1_Strong, PS4, PP4_Moderate . LINK:https://erepo.genome.network/evrepo/ui/classification/CA152950/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Consequence

GCK
NM_000162.5 missense

Scores

15
3
1

Clinical Significance

Pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 4.93
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 13 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.
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
GCKNM_000162.5 linkuse as main transcriptc.1112G>T p.Cys371Phe missense_variant 9/10 ENST00000403799.8 NP_000153.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkuse as main transcriptc.1112G>T p.Cys371Phe missense_variant 9/101 NM_000162.5 ENSP00000384247 P1P35557-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelAug 09, 2023The c.1112G>T variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to phenylalanine at codon 371 (p.(Cys371Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.931, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was hyperglycemia (PS4; PMID 24735133, internal lab contributors). This variant segregated with hyperglycemia with 12 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as either OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PP1_Strong, PS4, PP4_Moderate . -
Gestational diabetes Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoOct 23, 2020DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1112G>T, in exon 9 that results in an amino acid change, p.Cys371Phe. The p.Cys371Phe change affects a highly conserved amino acid residue located in a Hexokinase domain of the GCK protein that is known to be functional. The p.Cys371Phe substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in two families with MODY (PMID: 19790256). This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs587780343). Different sequence changes affecting the same amino acid residue (p.Cys371Arg, p.Cys371Trp, p.Cys371Trp) have also been described in patients with GCK-related MODY (PMID: 19790256) -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 03, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 129140). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 24735133; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 371 of the GCK protein (p.Cys371Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
.;D;D;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
.;.;H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-11
.;D;D;D;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;.;D;D;D;D
Vest4
0.94
MutPred
0.97
.;.;Loss of disorder (P = 0.1014);.;.;.;
MVP
0.98
MPC
2.7
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.99
gMVP
1.0

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: rs587780343; hg19: chr7-44185237; API