7-44147732-C-T

Variant names:

• chr7-44147732-C-T
• rs104894008
• NM_000162.5:c.781G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PM3 PP2 PP3 PS3_Moderate PM2_Supporting PP4_Moderate PS4 PS2 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP 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 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID:19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA126211/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 7.83
• Publications: 40 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 21 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• PM3: 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	c.781G>A	p.Gly261Arg	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.781G>A	p.Gly261Arg	missense_variant	Exon 7 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251056 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461202 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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: 52758

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:4

Apr 01, 2019

Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Using next-generation sequencing, we found the heterozygous variant in a patient under suspect of MODY. -Mean coverage: 122X; 98.4% of target-regions at 20X -

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2 -

Dec 30, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GCK c.781G>A variant is classified as Likely Pathogenic (PS3, PM2, PP3) The GCK c.781G>A variant is a single nucleotide change in exon 7/10 of the GCK gene, which is predicted to change the amino acid glycine at position 261 in the protein to arginine. This variant is absent from population databases (PM2). Well-established functional studies show a deleterious effect of this variant ( Gidh-Jain et al. (PMID:8446612) ) (PS3). Please note this variant has been previously reported in the literature as: NM_0001354800.1: c.781G>A, p.Gly261Arg. -

Aug 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

Jan 13, 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 261 of the GCK protein (p.Gly261Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant GCK-related conditions (PMID: 1502186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16135). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 10525657). For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 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)) Heterozygous individuals with this variant presented with clinical features of MODY, while homozygous individuals presented with permanent neonatal diabetes mellitus. This variant associates with MODY in multiple families. 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. Studies show this variant results in reduced kinase activity (PMID: 8446612, 19903754, 10525657). -

Jan 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect resulting in significantly decreased glucokinase activity compared to wildtype (PMID: 8446612, 25015100); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 9049484, 30191644, 21521320, 22611063, 10525657, 8446612, 1502186, 17573900, 27167055, 1464666, 10694920, 30663027, 25015100, 21518409, 22761713, 26552609, 8168652, 19903754, 34440516, 34496959, 36257325, 36208030, 36504295, ChoJ2022[Preprint], 37958824, 37240725, 36724243, 36418577, 22060211, 36342518, 35472491, 37101203) -

Monogenic diabetes Pathogenic:2

May 06, 2024

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.781G>A (p.Gly261Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal (IPR022673) 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 251056 control chromosomes. c.781G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (Stoffel_1992). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in negligible activity of mutant glucokinase when compared to wildtype (Davis_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10525657, 1502186).ClinVar contains an entry for this variant (Variation ID: 16135). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 12, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP 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 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2. -

Maturity onset diabetes mellitus in young Pathogenic:1

Aug 27, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G261R pathogenic mutation (also known as c.781G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 781. The glycine at codon 261 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families with a clinical diagnosis of maturity-onset diabetes of the young (MODY), and has been shown to segregate with disease (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Yorifuji T et al. Pediatr Diabetes, 2012 Feb;13:26-32). In one family, the proband was homozygous for p.G261R and presented with permanent neonatal diabetes mellitus; elevated fasting glucose was detected in four heterozygous family members: two sisters, the father with a history of diabetes, and the mother with a history of gestational diabetes (Bennett K et al. Pediatr Diabetes, 2011 May;12:192-6). In addition, functional studies have shown that p.G261R mutant GCK has significantly reduced enzymatic activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Beer NL et al. Diabetes Care, 2012 Jul;35:1482-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Maturity-onset diabetes of the young type 3 Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.6	.;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.94		.;Loss of glycosylation at S263 (P = 0.0679);.;.;.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894008; hg19: chr7-44187331;