7-44152420-C-T

Variant names:

• chr7-44152420-C-T
• rs193922289
• NM_000162.5:c.214G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3_Supporting PP2 PP3 PM2_Supporting PP4_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.214G>A variant in the glucokinase gene, GCK causes an amino acid change of glycine to arginine at codon 72 (p.(Gly72Arg)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copies in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 48 unrelated individuals with diabetes/hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 23 informative meioses in multiple families (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km was between 0.4-0.65, the p.Gly72Arg had a relative activity index (RAI) > 0.5 and a relative stability index (RSI) <=0.5 (PS3_Supporting; PMID:25015100). In summary, c.214G>A 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 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213771/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 7.90
• Publications: 34 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.214G>A	p.Gly72Arg	missense	Exon 3 of 10	NP_000153.1
	GCK	NM_033507.3		c.217G>A	p.Gly73Arg	missense	Exon 3 of 10	NP_277042.1
	GCK	NM_033508.3		c.211G>A	p.Gly71Arg	missense	Exon 4 of 11	NP_277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.214G>A	p.Gly72Arg	missense	Exon 3 of 10	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*212G>A		non_coding_transcript_exon	Exon 4 of 11	ENSP00000379142.4
	GCK	ENST00000395796.8	TSL:1	n.*212G>A		3_prime_UTR	Exon 4 of 11	ENSP00000379142.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251364 AF XY: 0.00000736

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7

Jul 12, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate increased activity compared to wild type as well as decreased thermal stability of the protein (PMID: 16731834, 25015100); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17389332, 18399931, 24735133, 29056535, 31216263, 21831042, 19187021, 25015100, 26669242, 12442280, 12955723, 20337973, 17573900, 10447526, 30191644, 30663027, 34108472, 16731834, 24411943, 33565752, 34462253, 34746319, 35472491, 36227502, 36257325, 36761491, 37008541, 36504295)

Jul 10, 2020

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.Gly72Arg variant substitutes the glycine with arginine at position 72 of the protein. This is a recurrent pathogenic variant that has been reported in the heterozygous state in multiple individuals with MODY (PMID: 19790256, PMID: 10447526, PMID: 12442280, PMID: 30191644 and others). This is not a common variant in the general population (observed in 1 of 251,364 alleles; gnomAD v2.1.1). The p.Gly72Arg variant has been experimentally demonstrated to reduce GCK catalytic activity (PMID: 19187021, PMID: 17389332)

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 12, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GCK c.214G>A; p.Gly72Arg variant (rs193922289) is reported in several individuals with MODY and segregates with disease in affected family members (Ates 2021, Cao 2002, Johnson 2019, Katashima 2021, Lehto 1999, Yalcintepe 2021). Multiple functional analyses of the variant protein demonstrate an effect on protein function (Arden 2007, Ralph 2009, Sagen 2006, Zelent 2011). This variant is also reported in ClinVar (Variation ID: 36209). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.994). Based on available information, this variant is considered to be pathogenic. References: Arden C et al. Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic beta-cells: evidence for cellular instability of catalytic activity. Diabetes. 2007 Jul;56(7):1773-82. PMID: 17389332. Ates EA et al. Genetic and Clinical Characterization of Patients with Maturity-Onset of Diabetes of the Young (MODY): Identification of Novel Variations. Balkan Med J. 2021 Sep;38(5):272-277. PMID: 34462253. Cao H et al. GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). Hum Mutat. 2002 Dec;20(6):478-9. PMID: 12442280. Johnson SR et al. Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. Pediatr Diabetes. 2019 Feb;20(1):57-64. PMID: 30191644. Katashima R et al. Identification of Novel GCK and HNF4a Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age. J Diabetes Res. 2021 Oct 29;2021:7216339. PMID: 34746319. Lehto M et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia. 1999 Sep;42(9):1131-7. PMID: 10447526. Ralph EC et al. Biochemical characterization of MODY2 glucokinase variants V62M and G72R reveals reduced enzymatic activities relative to wild type. Biochemistry. 2009 Mar 24;48(11):2514-21. PMID: 19187021. Sagen JV et al. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Diabetes. 2006 Jun;55(6):1713-22. PMID: 16731834. Yalcintepe S et al. The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region. J Clin Res Pediatr Endocrinol. 2021 Aug 23;13(3):320-331. PMID: 33565752 Zelent B et al. Mutational analysis of allosteric activation and inhibition of glucokinase. Biochem J. 2011 Dec 1;440(2):203-15. PMID: 21831042.

Dec 01, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 20, 2025

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 72 of the GCK protein (p.Gly72Arg). This variant is present in population databases (rs193922289, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 10447526, 12442280, 30259503, 30447144, 30663027, 31216263; internal data). ClinVar contains an entry for this variant (Variation ID: 36209). 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 expected to disrupt GCK protein function with a positive predictive value of 80%. Studies have shown that this missense change alters GCK gene expression (PMID: 16731834, 17389332). This variant disrupts the p.Gly72 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 31216263), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Monogenic diabetes Pathogenic:3

Jun 17, 2022

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.214G>A (p.Gly72Arg) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251464 control chromosomes. c.214G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2 (example, Mantovani_2003, Lehto_1999, Cao_2002, Pruhova_2010). 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. Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly72Arg variant in GCK has been reported in at least 12 individuals (including 2 Mediterranean, 2 Scandinavian, 2 Spanish, 1 Italian, 1 Czech, 1 Turkish, 1 Slovakian, 1 Norwegian, and 1 Asian individuals) with Monogenic Diabetes, segregated with disease in 6 affected relatives from 3 families (PMID: 27106716, 25015100, 22493702, 18399931, 10447526, 12955723, 20337973, 17573900, 15305805), and has been identified in 0.006155% (1/16248) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922289). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 36209). In vitro functional studies provide some evidence that the p.Gly72Arg variant may impact protein activity and interactions with a regulatory protein (PMID: 21831042, 22028181, 17389332, 19187021). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly72Arg is located in a region of GCK that is essential to ATP binding and associated with hypoglycemia, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (PMID: 15305805, 19187021). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PM1_Supporting (Richards 2015).

Aug 13, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.214G>A variant in the glucokinase gene, GCK causes an amino acid change of glycine to arginine at codon 72 (p.(Gly72Arg)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copies in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 48 unrelated individuals with diabetes/hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 23 informative meioses in multiple families (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km was between 0.4-0.65, the p.Gly72Arg had a relative activity index (RAI) > 0.5 and a relative stability index (RSI) <=0.5 (PS3_Supporting; PMID: 25015100). In summary, c.214G>A 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 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3, PP2.

Maturity-onset diabetes of the young type 2 Pathogenic:1

Jan 31, 2022

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GCK p.Gly72Arg variant is pathogenic for maturity-onset diabetes of the young (MODY), with functional studies demonstrating that Gly27Arg results in reduced glucokinase activity and loss of stabilising interactions with glucokinase regulatory protein (PMID: 19187021, 17389332).

Maturity onset diabetes mellitus in young Pathogenic:1

Nov 13, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G72R variant (also known as c.214G>A), located in coding exon 3 of the GCK gene, results from a G to A substitution at nucleotide position 214. The glycine at codon 72 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in numerous maturity onset diabetes of the young families (Lehto M et al. Diabetologia, 1999 Sep;42:1131-7; Cao H et al. Hum. Mutat., 2002 Dec;20:478-9; Mantovani V et al. Hum. Mutat., 2003 Oct;22:338; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Valent&iacute;nov&aacute; L et al. PLoS ONE, 2012 May;7:e34541; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40; Bansal V et al. BMC Med, 2017 12;15:213). In addition, kinetic studies demonstrated reduced thermal stability compared to wild type (Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). This amino acid position is highly 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.99		Loss of sheet (P = 0.1398)
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	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: rs193922289; hg19: chr7-44192019;