chr7-44147726-A-G

Variant names:

• chr7-44147726-A-G
• rs193922331
• NM_000162.5:c.787T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2 PM2_Supporting PP4_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.787T>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to proline at codon 263 (p.(Ser263Pro)) of NM_000162.5. This variant was identified in at least 14 unrelated individuals with hyperglycemia (PS4; PMID:32074423, internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.80e-7, which is below the threshold for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant segregated with diabetes/hyperglycemia, with at least 21 informative meioses in 9 families (PP1_Strong; PMID:32074423, internal lab contributors). 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 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 antibody negative) (PP4_Moderate; internal lab contributors). This variant has a REVEL score of 0.689, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and while the variant appears to result in thermal instability, the relative stability index was not calculated, therefore PS3_Supporting will not be applied (PMID:16731834).In summary, c.787T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP1_Strong, PP2, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152961/MONDO:0015967/086

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.326
• Publications: 18 publications found

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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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.
• 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	c.787T>C	p.Ser263Pro	missense_variant	Exon 7 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.787T>C	p.Ser263Pro	missense_variant	Exon 7 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461152 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726904

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000469 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Sep 27, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with MODY. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22820548, 22028181, 21921030) -

Sep 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with MODY in published literature (PMID: 25306193, 32074423, 12442280, 25555642); however, patient-specific clinical information not provided; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12442280, 15305805, 32041611, 21831042, 22820548, 21921030, 22028181, 16731834, 32074423, 25555642, 36257325, 25306193) -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 263 of the GCK protein (p.Ser263Pro). This variant is present in population databases (rs193922331, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 12442280, 25306193, 25555642, 32074423; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36258). 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 affects GCK function (PMID: 21921030, 22028181, 22820548). For these reasons, this variant has been classified as Pathogenic. -

Maturity-onset diabetes of the young type 2 Pathogenic:2

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Jun 09, 2017

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.787T>C variant in codon 263 (exon 7) of the glucokinase gene, GCK, results in the substitution of Serine to a Proline. The c.787T>C was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported to segregate with diabetes in a family whose clinical picture is consistent with Maturity-Onset Diabetes of the Young (MODY) (12442280). Functional analyses of this variant have demonstrated thermal instability, protein misfolding and aberrant dimerization (22820548;16731834). Additionally, multiple lines of computational evidence (SIFT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PS3, PM2, PP1, PP3 -

Maturity onset diabetes mellitus in young Pathogenic:2

Dec 20, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S263P variant (also known as c.787T>C), located in coding exon 7 of the GCK gene, results from a T to C substitution at nucleotide position 787. The serine at codon 263 is replaced by proline, an amino acid with similar properties. This variant was identified in two maturity-onset diabetes of the young families (Cao H et al. Hum. Mutat., 2002 Dec;20:478-9; Sagen JV et al. Diabetes, 2006 Jun;55:1713-22). When stably over expressed in HEK293 cells and MIN6 cells, this variant generated a misfolded protein with an increased rate of degradation and a propensity to self-associate and form dimers and aggregates (Negahdar M et al. Biochim. Biophys. Acta, 2012 Nov;1822:1705-15). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser262Pro variant in GCK has been reported in at least 3 individuals with suspicion for MODY and segregated with disease in at least 3 affected members of two families (Cao 2002, Sagen 2006, GeneDx personal communication). It has also been identified in 1/128844 European chromosomes by gnomAD (http://gnomad.broad institute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 36258). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. However, multiple in vitro functional studies suggest that this variant impacts protein function (Sag en 2006, Zelent 2011, Fenner 2011, Negahdar 2012, George 2014). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Ser262Pro variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PS4_Supporting. -

GCK-related disorder Pathogenic:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GCK c.787T>C variant is predicted to result in the amino acid substitution p.Ser263Pro. This variant has been repeatedly reported to be pathogenic for maturity-onset diabetes of the young (MODY) due to reduced thermal stability (S263P at Cao et al. 2002. PubMed ID: 12442280; McKinney JL et al 2004. PubMed ID: 15305805; Sagen JV et al 2006. PubMed ID: 16731834; García-Herrero CM et al 2006. PubMed ID: 17186219; Zelent B et al 2011. PubMed ID: 21831042; Negahdar et al. 2012. PubMed ID: 22820548; Bennett JT et al 2014. PubMed ID: 25555642). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Monogenic diabetes Pathogenic:1

Jun 27, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.787T>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to proline at codon 263 (p.(Ser263Pro)) of NM_000162.5. This variant was identified in at least 14 unrelated individuals with hyperglycemia (PS4; PMID: 32074423, internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.80e-7, which is below the threshold for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant segregated with diabetes/hyperglycemia, with at least 21 informative meioses in 9 families (PP1_Strong; PMID: 32074423, internal lab contributors). 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 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 antibody negative) (PP4_Moderate; internal lab contributors). This variant has a REVEL score of 0.689, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and while the variant appears to result in thermal instability, the relative stability index was not calculated, therefore PS3_Supporting will not be applied (PMID: 16731834). In summary, c.787T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP1_Strong, PP2, PP4_Moderate. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2 Pathogenic:1

Jan 05, 2022

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the exon 7 of GCK gene has been reported in multiple patients with hyperglycemia and found to be co-segregated with disease phenotype [PMID: 22820548, 16731834, 32074423] and was reported as pathogenic in a cohort study involving hypertriglyceridemia and familial hypercholesterolemia patients [PMID: 32041611]. In vitro functional studies demonstrated that p. Ser263Pro variant leads to protein misfolding, thermal instability and aberrant dimerization [PMID:22820548,16731834]. The variant has 0.000006570 allele frequency in the gnomAD(v3) database (1 out of 152218 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The identified variant has been reported in the ClinVar database as a Likely Pathogenic [Variation ID: 36258]. The variant affects a moderately conserved residue in the large hexokinase domain of the GCK protein [PMID: 31638168] and is predicted deleterious by multiple in silico tools (CADD score = 22.7, REVEL score = 0.689). Based on the available evidence, the heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the GCK gene is classified as ‘Likely Pathogenic’. -

Gestational diabetes Pathogenic:1

Nov 18, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.787T>C, in exon 7 that results in an amino acid change, p.Ser263Pro. The p.Ser263Pro change affects a poorly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser263Pro substitution. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0032% % (dbSNP rs193922331). This sequence change has been previously reported in patients with GCK-related hyperglycemia (PMIDs: 12442280, 16731834). Functional studies have also demonstrated that p.Ser263ro sequence change results in reduced protein misfolding and aberrant dimerization (PMIDs: 22820548, 16731834). These collective evidences indicate that this sequence change is the likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D;D;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.5	.;L;.;.;.
PhyloP100		0.33
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	.;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	.;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.048	B;B;B;B;.
Vest4		0.47
MutPred		0.79		.;Loss of glycosylation at S263 (P = 0.0429);.;.;.;
MVP		0.91
MPC		1.4
ClinPred		0.86	D
GERP RS		-0.043
Varity_R		0.90
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922331; hg19: chr7-44187325;