7-44153338-C-T

Variant names:

• chr7-44153338-C-T
• rs1057520109
• NM_000162.5:c.171G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_Moderate PM2_Supporting PP2 PP3 PP1 PS4_Moderate PS2

This summary comes from the ClinGen Evidence Repository: The c.171G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 57 (p.(Met57Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). 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 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID:24323243, internal lab contributors). In one of these individuals this variant was identified as a de novo occurrence with confirmed parental relationships and a clinical picture higly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L, HbA1c 5.6-7.6 and negative autoantibodies) (PS2, PP4_Moderate; PMID:24323243). This variant segregated with hyperglycemia, with 2 informative meioses in two families (PP1; internal lab contributors). In summary, c.170T>G 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, PP1, PP2, PP3, PP4_Moderate, PS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618473/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS2: 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.
• 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.171G>A	p.Met57Ile	missense_variant	Exon 2 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.174G>A	p.Met58Ile	missense_variant	Exon 2 of 10		NP_277042.1
GCK	NM_033508.3	c.168G>A	p.Met56Ile	missense_variant	Exon 3 of 11		NP_277043.1
GCK	NM_001354800.1	c.171G>A	p.Met57Ile	missense_variant	Exon 2 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.171G>A	p.Met57Ile	missense_variant	Exon 2 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Feb 28, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.171G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 57 (p.(Met57Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). 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 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24323243, internal lab contributors). In one of these individuals this variant was identified as a de novo occurrence with confirmed parental relationships and a clinical picture higly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L, HbA1c 5.6-7.6 and negative autoantibodies) (PS2, PP4_Moderate; PMID: 24323243). This variant segregated with hyperglycemia, with 2 informative meioses in two families (PP1; internal lab contributors). In summary, c.170T>G 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, PP1, PP2, PP3, PP4_Moderate, PS2). -

May 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK c.171G>A (p.Met57Ile) results in a conservative amino acid change located in the hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes (gnomAD). c.171G>A has been reported in the literature as a de novo occurrence in at least an individual affected with maturity-onset diabetes of the young (example: Stanik_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24323243). ClinVar contains an entry for this variant (Variation ID: 418225). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:2

May 22, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been confirmed to occur de novo in one individual with autosomal dominant maturity-onset diabetes of the young (MODY). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203) -

Jan 16, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 24323243) -

Maturity onset diabetes mellitus in young Pathogenic:1

Nov 11, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M57I variant (also known as c.171G>A), located in coding exon 2 of the GCK gene, results from a G to A substitution at nucleotide position 171. The methionine at codon 57 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported to occur de novo in a an individual with maturity-onset diabetes of the young (MODY) (Stanik J et al. Diabetologia. 2014;57:480-4). Based on internal structural analysis, p.M57I is predicted to be moderately destabilizing to the structure near residues involved in binding to glucokinase regulatory protein, and p.M57I is predicted to be more destabilizing than a nearby pathogenic variant (p.S263P) (Beck T et al. Biochemistry. 2013;52(36):6232-9). Other variants affecting this codon (p.M57R, c.170T>G and p.M57T, c.170T>C) have been detected in MODY cohorts however, clinical details were limited (Osbak KK et al. Hum Mutat. 2009;30(11):1512-26; Borowiec M et al. Clin Genet. 2012;82(6):587-90). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;H;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	.;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.013	.;D;D;D;D
Sift4G	Uncertain	0.049	D;T;D;T;D
Polyphen		0.99	D;D;D;D;.
Vest4		0.95
MutPred		0.80		.;Loss of disorder (P = 0.0294);.;.;Loss of disorder (P = 0.0294);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
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: rs1057520109; hg19: chr7-44192937;