rs777870079

Variant names:

• chr7-44145602-G-A
• rs777870079
• NM_000162.5:c.1148C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44145602-G-A
• chr7-44145602-G-C
• chr7-44145602-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP4_Moderate PM2_Supporting PS3_Moderate PP2 PP3 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1148C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to leucine at codon 383 (p. (Ser383Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (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 located in the larger hexokinase domain of the GCK gene (PMID:31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.831 which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.20, which is below the MDEP cutoff (<0.5) (Matschinsky FM, Magnuson MA (eds): Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front. Diabetes. Basel, Karger, 2004, vol 16, pp 92–109). This variant has been identified in at least 53 unrelated individuals with hyperglycemia and segregated with the phenotype, with 30 informative meioses in 49 families (PS4, PP1_Strong; PMID:28555465, 30663027, 34462253, 34746319, internal lab contributors). At least of of these patients had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative GAD-65 (PP4_Moderate; PMID:28555465). In summary, c.1148C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PS4, PP4_Moderate, PP2, PP1_Strong, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581499/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 2.43

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 15 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.
• 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.1148C>T	p.Ser383Leu	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1148C>T	p.Ser383Leu	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454900 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723714

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

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

Sep 09, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2017

Kangwon National University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glucokinase-maturityonset diabetes of the young (GCKMODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. Because people with GCK-MODY do not develop significant microvascular complications, treatment is not recommended except pregnancy. Glucose-lowering therapy is ineffective in people with GCK-MODY. -

Nov 08, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Dec 21, 2016

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 383 of the GCK protein (p.Ser383Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of GCK-related conditions (PMID: 12050210, 15841481, 17573900, 20337973, 22525692, 24918535, 28555465, 30447144, 30663027, 31216263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236014). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

May 24, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 12050210, 32533152, 19790256, 14517946, 24918535, 17573900, 11942313, 28555465, 30663027, 21348868, 20337973, 16963153, 16602010, 15841481, 32375122, 31216263, 33242514, 32041611) -

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.1148C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to leucine at codon 383 (p. (Ser383Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (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 located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.831 which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.20, which is below the MDEP cutoff (<0.5) (Matschinsky FM, Magnuson MA (eds): Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front. Diabetes. Basel, Karger, 2004, vol 16, pp 92-109). This variant has been identified in at least 53 unrelated individuals with hyperglycemia and segregated with the phenotype, with 30 informative meioses in 49 families (PS4, PP1_Strong; PMID: 28555465, 30663027, 34462253, 34746319, internal lab contributors). At least of of these patients had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative GAD-65 (PP4_Moderate; PMID: 28555465). In summary, c.1148C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PS4, PP4_Moderate, PP2, PP1_Strong, PM2_Supporting -

Mar 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK NM_000162.3:c.1148C>T (p.Ser383Leu) results in a non-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 was absent in 234324 control chromosomes. c.1148C>T has been reported in the literature in multiple individuals affected with features of Monogenic Diabetes (Maturity Onset Diabetes Of The Young 2) (example, PMID: 12050210, 28555465, 20337973, 36208343). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified 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

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4+PM2_Supporting+PP3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.98	D;.;D;D;P;D
Vest4		0.90
MutPred		0.95		.;.;Loss of disorder (P = 0.0297);.;.;.;
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.91
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: rs777870079; hg19: chr7-44185201;