rs1064794268

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.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, 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 identified in 7 unrelated individuals with hyperglycemia (PS4; PMID:1508276, 11079754, internal lab contributors). One 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 OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID:11508276, internal lab contributors). In summary, c.113A>C 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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618475/MONDO:0015967/086

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GCK
ENST00000403799.8 missense

Scores

8
6
5

Clinical Significance

Pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 1.47
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.113A>C p.Gln38Pro missense_variant 2/10 ENST00000403799.8 NP_000153.1
GCKNM_033507.3 linkuse as main transcriptc.116A>C p.Gln39Pro missense_variant 2/10 NP_277042.1
GCKNM_033508.3 linkuse as main transcriptc.110A>C p.Gln37Pro missense_variant 3/11 NP_277043.1
GCKNM_001354800.1 linkuse as main transcriptc.113A>C p.Gln38Pro missense_variant 2/11 NP_001341729.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkuse as main transcriptc.113A>C p.Gln38Pro missense_variant 2/101 NM_000162.5 ENSP00000384247 P1P35557-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461856
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 20, 2021Variant summary: GCK c.113A>C (p.Gln38Pro) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.113A>C has been reported in the literature in individuals affected with Monogenic Diabetes including in a pair of siblings as well as a reported de novo occurrence (Prisco_2000, Massa_2001, Velho_2004, Aloi_2017, Bitterman_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different amino acid change affecting the same codon (p.Gln38Leu) has been reported in association with monogenic diabetes (HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelMar 19, 2024The c.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, 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 identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 1508276, 11079754, internal lab contributors). One 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 OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors). In summary, c.113A>C 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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. -
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxMar 09, 2017The Q38P variant has been published previously in association with MODY, including an apparently de novo occurrence (Prisco et al., 2000; Massa et al., 2001; Osbak et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q38P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (Q38L) and in nearby residues (V33A, R36W/Q, M37R, E40K, M41T, R43S/G/C/P/H) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 01, 2024This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 38 of the GCK protein (p.Gln38Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (MODY) (PMID: 11079754, 11508276, 28726111, 36227502). ClinVar contains an entry for this variant (Variation ID: 420070). 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 with a negative predictive value of 80%. In 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. -
Maturity-onset diabetes of the young type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingTranslational Genomics Laboratory, University of Maryland School of MedicineJun 07, 2017The c.113A>C variant in codon 38 (exon 2) of the glucokinase gene, GCK, results in the substitution of Glutamine to Proline. The c.113A>C variant was previously identified in the patient's nephew, who has a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY). It was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in two patients with a MODY2 phenotype (11508276;11079754). Another variant at this codon, Gln38Leu, has been found to co-segregate with fasting hyperglycemia in a different family (K. Colclough, personal communication, April 10, 2017). Additionally, multiple lines of computational evidence (SIFT, LRT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD, GERP, PROVEAN) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4-mod, PM2, PP1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
.;D;.;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.83
T;T;.;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.6
.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.0
.;D;D;D;D
REVEL
Pathogenic
0.89
Sift
Benign
0.038
.;D;D;D;D
Sift4G
Benign
0.29
T;T;T;T;T
Polyphen
0.99
D;D;D;P;.
Vest4
0.94
MutPred
0.84
.;Gain of glycosylation at Q38 (P = 0.0262);.;.;Gain of glycosylation at Q38 (P = 0.0262);
MVP
0.99
MPC
2.3
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.96
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: rs1064794268; hg19: chr7-44192995; API