7-44146530-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4_ModeratePM2_SupportingPP2PP3PS4PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.952G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 318 (p.(Gly318Arg)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthemore, this variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491, and 36208343). This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325). Additionally, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID:31416898). In summary, c.952G>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 8/11/23): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367399913/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 7.76

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]

GCK links:

Genome browser will be placed here

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 rank	MANE	Protein	UniProt
GCK	NM_000162.5 link	c.952G>A	p.Gly318Arg	missense_variant	Exon 8 of 10	ENST00000403799.8	NP_000153.1	P35557-1Q53Y25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 link	c.952G>A	p.Gly318Arg	missense_variant	Exon 8 of 10	1	NM_000162.5	ENSP00000384247.3		P35557-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458148

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725650

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 12627330, 22493702, 28663157, 29207974). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585929). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 27, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 21348868, 33852230, 26641800, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 31416898, 30245511, 23433541, 36257325, 34440516, 34556497, 35472491, 36208343, 35737141, 22332836) -

Feb 16, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced affinity of the enzyme to glucose (PMID: 28842611). -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GCK: PS4, PM2, PM6, PP1, PP3 -

Monogenic diabetes

Pathogenic:3

Dec 23, 2021

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.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247788 control chromosomes. c.952G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes presenting as MODY2 (Maturity Onset Diabetes of the Young) (example, Thomson_2003, Pruhova_2003, Feigeriova_2006, Dustakova_2012, Valentinova_2012, Gal_2021). 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. 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 16, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.952G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 318 (p.(Gly318Arg)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthemore, this variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491, and 36208343). This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325). Additionally, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID: 31416898). In summary, c.952G>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 8/11/23): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. -

Jun 18, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pancytopenia-developmental delay syndrome

Pathogenic:1

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity-onset diabetes of the young type 2

Pathogenic:1

Dec 03, 2024

Department of Clinical Genetics, Medical University of Lodz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GCK-related disorder

Pathogenic:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GCK c.952G>A variant is predicted to result in the amino acid substitution p.Gly318Arg. This variant is predicted to alter splicing by strengthening a cryptic splice site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751; Alamut Visual v1.6.1). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported in individuals with maturity-onset diabetes of the young and noted to segregate with disease in several families (Pruhova et al. 2003. PubMed ID: 12627330; Dusatkova et al. 2012. PubMed ID: 22332836; Wędrychowicz et al. 2017. PubMed ID: 28663157). In addition, it has been reported as a founder variant in individuals of Czech ancestry (Dusatkova et al. 2012. PubMed ID: 22332836). A different missense variant affecting the same amino acid (p.Glu318Ala), has been reported in an individual with maturity-onset diabetes of the young (Gloyn. 2003. PubMed ID: 14517946). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;.;.

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

.;M;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.3

.;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.93

MutPred

0.92

.;Gain of solvent accessibility (P = 0.0078);.;.;.;

MVP

0.94

MPC

2.2

ClinPred

1.0

GERP RS

3.9

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.71

Position offset: -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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over