rs762263694

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS2_ModeratePP2PP3PP4PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.106G>T variant in the glucokinase gene,GCK, causes an amino acid change of arginine to tryptophan at codon 36 (p.(Arg36Trp)) of NM_000162.5. While the Popmax filtering allele frequency is 0.000002920 (European non-Finnish population), which is less than the MDEP cutoff for PM2_Supporting, there are two copies of the variant in the African/African American subpopulation; therefore, PM2_Supporting cannot be applied, and PS4 cannot be applied regardless of the number of cases. 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 0.911, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:16965331). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for GCK-MODY (PS2_Moderate; PMID:8168652). This variant segregated with diabetes, with five informative meioses in three families with MODY (PP1_Strong; PMIDs: 17573900, 23433541, 33477506). In summary, c.106C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PS2_Moderate, PP1_Strong, LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239720/MONDO:0015967/086

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 1.07

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

hyperinsulinism due to glucokinase deficiency
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
maturity-onset diabetes of the young type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
transient neonatal diabetes mellitus
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
permanent neonatal diabetes mellitus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GCK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PS2

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
GCK	NM_000162.5 link	c.106C>T	p.Arg36Trp	missense_variant	Exon 2 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3 link	c.109C>T	p.Arg37Trp	missense_variant	Exon 2 of 10		NP_277042.1
GCK	NM_033508.3 link	c.103C>T	p.Arg35Trp	missense_variant	Exon 3 of 11		NP_277043.1
GCK	NM_001354800.1 link	c.106C>T	p.Arg36Trp	missense_variant	Exon 2 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 link	c.106C>T	p.Arg36Trp	missense_variant	Exon 2 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251440

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41410

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 2

Pathogenic:4

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM2, PP3, PP1_Strong, PS4, PM5, PP4, PP2, PS3 -

Aug 22, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2017

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg36Trp variant substitutes the arginine with tryptophan at amino acid position 36 in the glucokinase protein. This is a recurrent variant that has been reported in the heterozygous state in multiple unrelated individuals with GCK-related MODY (PMID: 35592779 and others). The p.Arg36Trp variant is not common in the general population (observed in 4 of 282,826 alleles; gnomAD v2.1.1). This amino acid position is highly conserved. The p.Arg36Trp variant does not impact kinetics or enzymatic stability of the glucokinase enzyme and is thought to impact protein-protein interactions (PMID: 10426385). -

not provided

Pathogenic:4

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GCK c.106C>T; p.Arg36Trp variant (rs762263694) is reported in the literature in numerous individuals with a suspicion or diagnosis of MODY, including cosegregation with disease in multiple families and a de novo occurrence in at least one affected individual (Butnariu 2024, Estalella 2007, Giuffrida 2013, Hager 1994, Ivanoshchuk 2021, Mirshahi 2022, Vits 2006). This variant is found in the general population with an overall allele frequency of 0.001% (4/282,826 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.911). Based on available information, this variant is considered to be pathogenic. References: Butnariu LI et al. The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients. Int J Mol Sci. 2024 Jun 7;25(12):6318. PMID: 38928025. Estalella I et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf). 2007 Oct;67(4):538-46. PMID: 17573900. Giuffrida FM et al. A novel glucokinase deletion (p.Lys32del) and five previously described mutations co-segregate with the phenotype of mild familial hyperglycaemia (MODY2) in Brazilian families. Diabetes Res Clin Pract. 2013 May;100(2):e42-5. PMID: 23433541. Hager J et al. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes. 1994 May;43(5):730-3. PMID: 8168652. Ivanoshchuk DE et al. The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients. J Pers Med. 2021 Jan 18;11(1):57. PMID: 33477506. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Vits L et al. Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. Clin Genet. 2006 Oct;70(4):355-9. PMID: 16965331. -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 36 of the GCK protein (p.Arg36Trp). This variant is present in population databases (rs762263694, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 8168652, 17573900, 21348868, 22493702; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431973). 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%. Experimental studies have shown that this missense change does not substantially affect GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic. -

Dec 12, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is statistically more frequent in individuals with MODY than in the general population and/or healthy controls. This variant has been identified in at least one individual with clinical features of MODY, including an apparent de novo in one individual. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging. -

May 08, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24097065, 28012402, 24430320, 10426385, 14517946, 23433541, 12955723, 21348868, 21521320, 22540858, 16965331, 25555642, 30155490, 22389783, 33477506, 29056535, 38054414, 35218126, 24918535, 17573900, 36257325, 34496959, 16602010, 35592779, 36208030, 36178555, 36208343, 8168652, 36836406, 27935851, 39859454, 38745742, 38928025, Topcu2024[CaseReport], 39504571, Atava2024[CaseReport]) -

Maturity onset diabetes mellitus in young

Pathogenic:2

Aug 02, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R36W pathogenic mutation (also known as c.106C>T), located in coding exon 2 of the GCK gene, results from a C to T substitution at nucleotide position 106. The arginine at codon 36 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with maturity-onset diabetes of the young (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). Functional analysis of this alteration did not show an impact on kinetic activity or thermal stability; however, impact to protein-protein interactions was not assessed (Miller SP et al. Diabetes, 1999 Aug;48:1645-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jul 20, 2018

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.106C>T variant (rs762263694) is located in exon 2 of the GCK gene. The C to T transition results in the substitution of arginine for tryptophan at amino acid position 36 of the glucokinase protein. This same variant, as well as a different missense change involving the same amino acid residue (p.Arg36Gln), has been reported in the heterozygous state in several individuals with MODY (PMIDs: 8168652, 25555642, 24097065, 22540858 and others). This is a rare variant in the general population (GnomAD), and the substitution occurs at a position that is highly conserved across species. -

GCK-related disorder

Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GCK c.106C>T variant is predicted to result in the amino acid substitution p.Arg36Trp. This variant has been reported in many individuals with maturity onset diabetes of the young (MODY) (see for example, Table S1, Osbak et al. 2009. PubMed ID: 19790256; Passanisi et al. 2021. PubMed ID: 34496959; Santos Monteiro et al. 2022. PubMed ID: 36208343) and was reported in the de novo state in one of the families (Family F547 at Hager et al. 1994. PubMed ID: 8168652). It was found to segregate with GCK-related disease in at least 3 families (Hager et al. 1994. PubMed ID: 8168652; Giuffrida FM et al 2013. PubMed ID: 23433541; InternalData, PreventionGenetics). A functional study found that this variant had similar kinetic activity and stability compared to wild type; however, this study did not assess potential effects on protein-protein interactions (Miller et al. 1999. PubMed ID: 10426385). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. An alternate nucleotide change, p.Arg36Gln, has been reported in individuals with MODY (Osbak et al. 2009. PubMed ID: 19790256; Marucci et al. 2022. PubMed ID: 36227502). This variant is interpreted as likely pathogenic by the ClinGen Monogenic Diabetes Variant Curation Expert Panel in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/431973/). In summary, this variant is interpreted as likely pathogenic. -

Monogenic diabetes

Pathogenic:1

Oct 10, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.106G>T variant in the glucokinase gene,GCK, causes an amino acid change of arginine to tryptophan at codon 36 (p.(Arg36Trp)) of NM_000162.5. While the Popmax filtering allele frequency is 0.000002920 (European non-Finnish population), which is less than the MDEP cutoff for PM2_Supporting, there are two copies of the variant in the African/African American subpopulation; therefore, PM2_Supporting cannot be applied, and PS4 cannot be applied regardless of the number of cases. 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 0.911, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 16965331). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for GCK-MODY (PS2_Moderate; PMID:8168652). This variant segregated with diabetes, with five informative meioses in three families with MODY (PP1_Strong; PMIDs: 17573900, 23433541, 33477506). In summary, c.106C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PS2_Moderate, PP1_Strong, -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;D;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D;.;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

.;M;.;.;.

PhyloP100

1.1

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

.;D;D;D;D

REVEL

Pathogenic

0.91

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

0.83

MutPred

0.87

.;Loss of ubiquitination at K31 (P = 0.0331);.;.;Loss of ubiquitination at K31 (P = 0.0331);

MVP

0.99

MPC

2.3

ClinPred

0.99

GERP RS

1.9

Varity_R

0.91

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over