rs1057524904

chr7-44147765-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.748C>T(p.Arg250Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:2
• Conservation: PhyloP100: 5.71

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44147764-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435311.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 7-44147765-G-A is Pathogenic according to our data. Variant chr7-44147765-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 393451.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.748C>T	p.Arg250Cys	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.98+17G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.748C>T	p.Arg250Cys	missense_variant	7/10	1	NM_000162.5	P1

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

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:9 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:3

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. -
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, 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. -

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

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	Identified in unrelated patients with suspected MODY, hyperglycemia, or diabetes, however, patient-specific clinical information not provided (Pinterova et al., 2007; Lorini et al., 2009; Ma et al., 2019; Bonnefond et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19069349, 30245511, 20337973, 19790256, 33046911, 28842611, 32375122, 17204055, 19564454) -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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. -

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
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
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
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

Other links and lift over

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