rs1057524904

Positions:

chr7-44147765-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP1_StrongPP4_ModeratePP2PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.748C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 250 (p.(Arg250Cys)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK: This variant was identified in 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 30245511, 17204055, 19069349, 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 and 3 generation family history of diabetes/hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; PMID:30245511, 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.944 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.748C>T 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 8/11/2023): PM2_Supporting, PS4, PP4_Moderate, PP1_Strong, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16609268/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GCK
ENST00000403799.8 missense

Scores

12

6

1

Clinical Significance

Pathogenic reviewed by expert panel P:11U:1

Conservation

PhyloP100: 5.71

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:

LOC105375258 (HGNC:):

LOC105375258 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	7/10	ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3 linkuse as main transcript	n.98+17G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	7/10	1	NM_000162.5	ENSP00000384247	P1	P35557-1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461280

Hom.:

0

Cov.:

32

AF XY:

0.00000275

AC XY:

2

AN XY:

726972

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2023	Variant summary: GCK c.748C>T (p.Arg250Cys) results in a non-conservative amino acid change in 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 251252 control chromosomes. c.748C>T has been reported in the literature in multiple individuals affected with features of and/or meeting diagnostic criteria for Monogenic Diabetes/Maturity Onset Diabetes Of The Young 2 (MODY2) (example, Pinterova_2007, Milenkovic_2008, Pruhova_2010, Pihoker_2013, Huang_2018, Ma_2019, Saint-Martin_2021). The variant co-segregated with disease in at-least one of these reports (Ma_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30155490, 30245511, 19069349, 23771925, 17204055, 20337973, 34556497). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments citing overlapping evidence utilized in the context of this evaluation (P/LP, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Sep 09, 2016	The c.748C<T variant in codon 250 (exon 7) of the glucokinase gene, GCK, results in the substitution of Arginine to Cysteine. The c.748C<T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in the literature in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (Milenkovic, et al. 2008, 17204055, 19790256), with evidence of co-segregation with diabetes in one family (Colclough & Ellard, personal communication). A different amino acid substitution at this residue, p.Arg250Pro, was identified in a child with incidental hyperglycemia (19564454). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4, PM2, PP1, PP3 -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Oct 25, 2023	The c.748C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 250 (p.(Arg250Cys)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK: This variant was identified in 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 30245511, 17204055, 19069349, 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 and 3 generation family history of diabetes/hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; PMID: 30245511, 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.944 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.748C>T 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 8/11/2023): PM2_Supporting, PS4, PP4_Moderate, PP1_Strong, PP2, PP3. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the GCK protein (p.Arg250Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 17204055, 19069349, 23771925, 30155490, 30245511, 36257325; Invitae). ClinVar contains an entry for this variant (Variation ID: 393451). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. This variant disrupts the p.Arg250 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 19564454, 30592380), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2020	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant did not appear to affect the function of the protein when compared to wild-type; however, not all possible impacts on the protein were assayed, such as inhibitor binding or thermostability (PMID: 28842611). Computational tools predict that this variant is damaging. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2024	Identified in unrelated patients with suspected MODY, hyperglycemia, or diabetes, however, patient-specific clinical information not provided (PMID: 17204055, 19564454, 30245511, 33046911); 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 supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19069349, 30245511, 20337973, 19790256, 33046911, 28842611, 32375122, 19564454, 36208030, 17204055, 36257325, 34556497) -

Maturity-onset diabetes of the young type 2

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Sep 21, 2017	The c.748C<T variant in codon 250 (exon 7) of the glucokinase gene, GCK, results in the substitution of Arginine to Cysteine. The c.748C<T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in the literature in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (Milenkovic, et al. 2008, 17204055, 19790256), with evidence of co-segregation with diabetes in one family (Colclough & Ellard, personal communication). A different amino acid substitution at this residue, p.Arg250Pro, was identified in a child with incidental hyperglycemia (19564454). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4, PM2, PP1, PP3 -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg250Cys variant in GCK has been reported in at least 5 families with MODY (PMID: 15448103, 20337973, 19790256) and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 393451) as likely pathogenic by Translational Genomics Laboratory and as a VUS by Athena Diagnostics Inc. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PS4, PP1_Strong, PP4_Moderate, PM2, PP2, PP3 -

Maturity onset diabetes mellitus in young

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2018	The p.R250C variant (also known as c.748C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 748. The arginine at codon 250 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first reported in a Czech individual with a clinical diagnosis of MODY and was subsequently reported in three additional MODY families (Pinterova D et al. Clin. Genet., 2007 Jan;71:95-6; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Arg249Cys (also known as p.Arg250Cys) variant in GCK has been reported in at least 6 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 3 affected individuals from 1 family (Pruhova 2010 PMID: 20337973, Pinterova 2007 PMID: 17204055, Milenković 2008 PMID: 19069349, Osbak 2009 PMID: 19790256, Ma 2019 PMID: 30245511). This variant has also been reported in ClinVar (Variation ID 393451). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PP1. -

GCK-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2024

The GCK c.748C>T variant is predicted to result in the amino acid substitution p.Arg250Cys. This variant has been reported in multiple unrelated families with hyperglycemia and/or MODY (Pinterova et al. 2007. PubMed ID: 17204055; Supp. Table S1, Osbak et al. 2009. PubMed ID: 19790256; Ma Y et al 2018. PubMed ID: 30245511). Of note, a different change at the same codon (c.749G>C, p.Arg250Pro) has been also reported in MODY (Supp. Table S1, Osbak et al. 2009. PubMed ID: 19790256). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been classified as pathogenic by ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/393451/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

35

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

.;D;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

D

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Pathogenic

0.36

D

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.1

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

T

PROVEAN

Pathogenic

-6.2

.;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.97

MutPred

0.87

.;Loss of disorder (P = 0.0654);.;.;.;

MVP

0.96

MPC

2.5

ClinPred

1.0

D

GERP RS

5.3

Varity_R

0.90

gMVP

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057524904; hg19: chr7-44187364; COSMIC: COSV60788551; COSMIC: COSV60788551;