rs80356655

Positions:

• chr7-44147830-G-A

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS4 PS2 PM3_Supporting PP1_Strong PS3_Supporting PP4_Moderate PM1 PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.683C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 228 (p.(Thr228Met)) 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 resides in an amino acid that directly binds glucose and ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In an assay in which the ATPkm was above the MDEP threshold for evaluation of relative activity index (RAI), the Kcat/S0.5 ratio of the Thr228Met variant was 0.0001, which is less than 0.5 of wild type (PS3_Supporting; PMID:11372010). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed 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 at least 26 unrelated individuals with hyperglycemia (PS4; PMIDs: 21720051, 2721189, 36836406, 36723869, 32741144, 34756319, 11372010, 1502186, 31639168, 24323243, internal lab contributors). At least 2 of these individuals had 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; PMID:36723869). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; PMID:24323243). This variant has been detected in one individual with neonatal diabetes who was found to be homozygous for the c.683C>T variant (PM3_Supporting; PMID:11372010). In summary, c.683C>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, approved 8/11/2023): PS4, PS2, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA260620/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 9.94

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 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.
• PM1: 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.683C>T	p.Thr228Met	missense_variant	7/10	ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3	n.98+82G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.683C>T	p.Thr228Met	missense_variant	7/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250034 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726816

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 24, 2023	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with MODY, has been confirmed to occur de novo in one individual, and appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8446612, 10525657, 21569204) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2022	Published functional studies demonstrate that p.(T228M) nearly eliminates the catalytic activity of the GCK protein (Njolstad et al., 2001; Molnes et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9049484, 28395978, 17573900, 21978167, 17937063, 29056535, 24323243, 31576961, 1502186, 22335469, 14517946, 12955723, 18298419, 21569204, 24735133, 11372010, 8446612, 31638168, 31957151, 32792356, 32741144, 33409956, 34556497, 34746319, 34440516) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 228 of the GCK protein (p.Thr228Met). 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 autosomal dominant maturity-onset diabetes of the young (PMID: 22335469, 24323243, 31638168). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16134). 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) has been performed at Invitae 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: 8446612). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2019	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.683C>T, in exon 7 that results in an amino acid change, p.Thr228Met. This sequence change has been described in the gnomAD database in the heterozygous state in a single individual (dbSNP rs80356655). This pathogenic sequence change has previously been described in five affected family members with a GCK-MODY phenotype, and was absent from unaffected family members (PMIDs: 1502186). PMID: 11372010, reported this sequence change in the homozygous state in a patient with permanent neonatal diabetes with complete glucokinase deficiency; the parents, who each carried this sequence change, had impaired glucose tolerance or impaired fasting glucose. In vitro functional analysis of the p.Thr228Met variant demonstrated that this variant nearly abolished the catalytic activity of glucokinase (PMID: 11372010). Other pathogenic sequence changes affecting the same amino acid residue (p.Thr228Ala, p.Thr228Arg, p.Thr228Lys) have been described in patients with GCK-MODY (PMIDs: 12955723, 19790256). The p.Thr228Met change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Thr228Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -

Maturity-onset diabetes of the young type 2 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 24, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2022	- -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Permanent neonatal diabetes mellitus 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 24, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2022	- -

Maturity onset diabetes mellitus in young Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Thr227Met variant in GCK has been previously identified in at least 8 individuals with maturity-onset diabetes of the young (MODY), was de novo in at least one individual, and segregated with disease in affect relatives (Estalella 2007 PMID: 17573900; Stern 2007 PMID: 17937063; Delvecchio 2013 PMID: 22335469; Stanik 2014 PMID: 24323243; Costantini 2015 PMID: 24735133; Aykut 2018 PMID: 29056535; Glotov 2019 PMID: 31638168; Xu 2020 PMID: 31957151). In addition, this variant has been identified in individividuals with type 2 diabetes, gestational diabetes, and in the homozygous state in neonatal diabetes (Kousta 2001 PMID: 11553210; Njølstad 2001 PMID:11372010; Yokota 2011 PMID: 21720051). This variant has been identified in 0.003% (1/34570) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 16134). Functional studies provide evidence that this variant impacts protein function (Molnes 2011 PMID: 21569204; Njølstad 2001 PMID:11372010; Gidh-Jain 1993 PMID: 8446612; Stoffel 1992 PMID: 1502186), and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant (p.Thr228Ala) has been identified in individuals with monogenic diabetes. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4_Moderate; PM2; PM5_Supporting; PS2; PS3_Supporting; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2016	The p.T228M pathogenic mutation (also known as c.683C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 683. The threonine at codon 228 is replaced by methionine, an amino acid with similar properties. This mutation was first reported in three MODY families; of the family members available for testing, this mutation was identified in all of the affected individuals and in none of the unaffected individuals (Stoffel M, Proc. Natl. Acad. Sci. U.S.A. 1992 Aug; 89(16):7698-702). In another study, a proband with permanent neonatal diabetes was found to be homozygous for this mutation; both mother and father were confirmed heterozygous and had impaired fasting glucose and impaired glucose tolerance, respectively (Njølstad PR, N. Engl. J. Med. 2001 May; 344(21):1588-92). Based on the supporting evidence, p.T228M is interpreted as a disease-causing mutation. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2022

- -

GCK-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The GCK c.683C>T variant is predicted to result in the amino acid substitution p.Thr228Met. This variant has been repeatedly reported to be pathogenic for MODY (see for example Stoffel et al. 1992. PubMed ID: 1502186; Gidh-Jain et al. 1993. PubMed ID: 8446612; Stanik. 2014. PubMed ID: 24323243; Costantini et al. 2015. PubMed ID: 24735133; Glotov et al. 2019. PubMed ID: 31638168). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Feb 28, 2024

The c.683C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 228 (p.(Thr228Met)) 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 resides in an amino acid that directly binds glucose and ATP, which is defined as critical for the protein's function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In an assay in which the ATPkm was above the MDEP threshold for evaluation of relative activity index (RAI), the Kcat/S0.5 ratio of the Thr228Met variant was 0.0001, which is less than 0.5 of wild type (PS3_Supporting; PMID: 11372010). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed 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 at least 26 unrelated individuals with hyperglycemia (PS4; PMIDs: 21720051, 2721189, 36836406, 36723869, 32741144, 34756319, 11372010, 1502186, 31639168, 24323243, internal lab contributors). At least 2 of these individuals had 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; PMID: 36723869). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; PMID: 24323243). This variant has been detected in one individual with neonatal diabetes who was found to be homozygous for the c.683C>T variant (PM3_Supporting; PMID: 11372010). In summary, c.683C>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, approved 8/11/2023): PS4, PS2, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting. -

Hyperinsulinism due to glucokinase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	.;H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	.;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.96
MutPred		0.98		.;Gain of catalytic residue at M224 (P = 0.0301);.;.;.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
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: rs80356655; hg19: chr7-44187429;