rs1057524903

Variant names:

• chr7-44146466-T-C
• rs1057524903
• NM_000162.5:c.1016A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5_Supporting PP2 PP3 PP1 PS3_Moderate PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.1016A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 339 (p.(Glu339Gly)) 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 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; ClinVar: 393450, PMIDs: 18399931, 16731834, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 1 family (PP1; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.06, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID:16731834). Another missense variant, c.1015G>A p.Glu339Lys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1016A>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): PS4, PS3_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16609267/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.85
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1016A>G	p.Glu339Gly	missense_variant	Exon 8 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1016A>G	p.Glu339Gly	missense_variant	Exon 8 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 242508 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Feb 28, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1016A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 339 (p.(Glu339Gly)) 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 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; ClinVar: 393450, PMIDs: 18399931, 16731834, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 1 family (PP1; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.06, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). Another missense variant, c.1015G>A p.Glu339Lys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1016A>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): PS4, PS3_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PP1. -

Jun 03, 2016

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1016A>G variant in codon 339 (exon 8) of the glucokinase gene, GCK, results in the substitution of Glutamic acid to Glycine. This variant was originally reported to co-segregate with diabetes in a Norwegian family with a phenotype consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (16731834). It was subsequently shown to track with diabetes in six additional Norwegian families (18399931). Functional studies on recombinant p.(Glu339Gly) showed reduced enzyme activity and decreased affinity for glucose (16731834). A different amino acid substitution at this residue, p.(Glu339Lys), was found to track with the MODY2 phenotype across three generations of a Chinese family (21104275). Functional studies on p.(Glu339Lys) demonstrated decreased protein yield, lower glucose and ATP affinity, and decreased thermal stability compared to wildtype (21104275). The c.1016A>G variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, MutationAssessor, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS3, PM2, PM5, PP1, PP3 -

not provided Pathogenic:1

Oct 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced enzyme activity and reduced glucose affinity compared to wildtype (Sagen et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein function; In silico analysis supports that this variant has a deleterious effect on splicing; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 36504295, 22335469, 18399931, 16731834, 21104275, 19790256, 29927023, 36835446, 22389783, 24804978) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.4	.;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.90
MutPred		0.95		.;Loss of catalytic residue at E339 (P = 0.1014);.;.;.;
MVP		0.97
MPC		1.5
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.059	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057524903; hg19: chr7-44186065;