7-44149763-C-T

Position:

• chr7-44149763-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PS4 PP1_Strong PP4_Moderate PP2 PP3 PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) 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 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with 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 negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID:10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0​). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213827/MONDO:0015967/086

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.91

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 17 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.
• PM1: 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	c.676G>A	p.Val226Met	missense_variant	6/10	ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3	n.294C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.676G>A	p.Val226Met	missense_variant	6/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PS4, PP1_Strong, PS3_Moderate, PM2, PP2, PP4_Moderate, PP3, PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Oct 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 19, 2016	- -

Maturity onset diabetes mellitus in young Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2021	The p.Val225Met variant in GCK has been reported in >15 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 8 affected members across 6 families (Velho 1997, Pruhova 2003, Henderson 2007, Delvecchio 2014, Alkorta-Aranburu 2014, Raimondo 2014, Bennett 2015; note that most studies report this variant as p.Val226Met). This variant has also been identified in 0.002% (2/113710) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact to protein function (Davis 1999, Miller 1999, Raimondo 2014). Furthermore, multiple amino acid changes at the same position (p.Val225Glu, p.Val225Leu) have been reported in individuals with MODY, suggesting that changes to this position may not be tolerated. Finally, this variant as been reported as Pathogenic in ClinVar (Variation ID 36243). In summary, the p.Val225Met variant meets criteria to be classified as pathogenic for autosomal dominant MODY based on case observations, segregation studies, low frequency in controls, and functional evidence. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2020	The p.V226M variant (also known as c.676G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 676. The valine at codon 226 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in multiple individuals with maturity-onset diabetes of the young (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Vits L et al. Clin. Genet., 2006 Oct;70:355-9; Henderson M et al. Mol. Genet. Metab., 2007 Jan;90:87-92; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Raimondo A et al. Hum. Mol. Genet., 2014 Dec;23:6432-40). In addition, in vitro analyses by multiple groups have suggested that this variant affects enzyme kinetics including reduced activity (Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Davis EA et al. Diabetologia, 1999 Oct;42:1175-86; 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Dec 12, 2017	The c.676G>A (p.Val226Met, rs148311934) variant in exon 6 of GCK is a known pathogenic variant that has been reported in the medical literature (PMID: 17079173). This G to A transition results in the substitution of valine to methionine at amino acid position 226, which results in reduced enzymatic activity of glucokinase (PMID: 25015100). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 10, 2022	This is reported to be a founder variant in the Quebec region of Canada (PMID: 17079173), and is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant resulted in reduced ATP affinity and catalytic activity that could be due to increased protein instability (PMID: 10426385, 10525657, 25015100). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Published functional studies demonstrate a damaging effect leading to decreased enzyme activity of the glucokinase protein and may cause a milder phenotype by simultaneously increasing its stability (Davis et al., 1999; Raimondo et al., 2014); Not observed at a 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10426385, 25414397, 25306193, 25555642, 10525657, 20337973, 27080136, 27634015, 26897468, 16965331, 17079173, 9049484, 31957151, 32041611, 34108472, 25015100, 21569204, 22101819) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the GCK protein (p.Val226Met). This variant is present in population databases (rs148311934, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 9049484, 12627330, 17079173, 19790256, 22335469, 25414397, 25555642, 31957151). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36243). 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%. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385, 10525657). For these reasons, this variant has been classified as Pathogenic. -

Monogenic diabetes Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: GCK c.676G>A (p.Val226Met) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes (gnomAD). c.676G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (example: Velho_1997, Pruhova_2010, Vits_2006). These data indicate that the variant is very likely to be associated with disease. Multiple reports have provided experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Examples: Davis_ 1999 and Miller_1999). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Aug 13, 2023	The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) 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 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with 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 negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID: 10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1. -

GCK-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The GCK c.676G>A variant is predicted to result in the amino acid substitution p.Val226Met. This variant is well-documented as pathogenic for autosomal dominant maturity-onset diabetes of the young (MODY), and functional studies support its pathogenicity (Velho et al. 1997. PubMed ID: 9049484; Miller et al. 1999. PubMed ID: 10426385; Raimondo et al. 2014. PubMed ID: 25015100). This variant has been commonly found in MODY patients of French-Canadian origin (Raimondo et al. 2014. PubMed ID: 25015100). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	.;N;N;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.86		.;Gain of loop (P = 0.2045);.;.;.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.86
gMVP		0.99

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: rs148311934; hg19: chr7-44189362; COSMIC: COSV60787716; COSMIC: COSV60787716;