7-44149778-C-T

Variant names:

• chr7-44149778-C-T
• rs193922317
• NM_000162.5:c.661G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PP3 PM2_Supporting PP4_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.661A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 221 (p.(Glu221Lys)) 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 VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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. This variant was identified in 4 unelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMID:23295292, internal lab contributors). This variant has been identified in 25 unrelated individuals with hyperglycemia and segregated with the phenotype, with 17 informative meioses in at least 7 families (PS4, PP1_Strong; PMIDs: 10694920, 12955723, 31658956, 34462253, 35592779, 35733065, 23295292, and 30592380). A relative activity index (RAI) was calculated for this variant but the wild type parameters are outside of MDEP's recommendations; therefore, this data cannot be used towards PS3 (PMID:30592380). In summary, c.661A>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, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213824/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.91
• Publications: 18 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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• 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.661G>A	p.Glu221Lys	missense_variant	Exon 6 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.661G>A	p.Glu221Lys	missense_variant	Exon 6 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461780 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 221 of the GCK protein (p.Glu221Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 23295292, 26226118, 31216263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36241). 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: 30592380). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a moderate decrease in enzymatic activity (PMID: 30592380); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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; This variant is associated with the following publications: (PMID: 23295292, 30592380, 29056535, 10694920, 28012402, 14517946, 34462253, 28170077, 12955723, 32375122, 26226118, 25555642, 33031055, 31658956, 31216263, 11508276, 35472491, 36257325, 35592779, 36208030, 35733065) -

Aug 14, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.661A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 221 (p.(Glu221Lys)) 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 VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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. This variant was identified in 4 unelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMID: 23295292, internal lab contributors). This variant has been identified in 25 unrelated individuals with hyperglycemia and segregated with the phenotype, with 17 informative meioses in at least 7 families (PS4, PP1_Strong; PMIDs: 10694920, 12955723, 31658956, 34462253, 35592779, 35733065, 23295292, and 30592380). A relative activity index (RAI) was calculated for this variant but the wild type parameters are outside of MDEP's recommendations; therefore, this data cannot be used towards PS3 (PMID: 30592380). In summary, c.661A>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, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. -

Feb 24, 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 c.661G>A (p.Glu221Lys) results in a conservative amino acid change in 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 251548 control chromosomes (gnomAD, Guazzini_1998). c.661G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (Guazzini_1998, Mantovani_2003, Caetano_2012, Wang_2019), and has been observed segregating with disease within families (Guazzini_1998, Caetano_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. Wang_2019 found that the relative activity level of the variant protein was 47%. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP1_Strong, PS4, PP4_Moderate, PP2, PS3 -

Maturity onset diabetes mellitus in young Pathogenic:1

Apr 18, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E221K pathogenic mutation (also known as c.661G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 661. The glutamic acid at codon 221 is replaced by lysine, an amino acid with similar properties. This mutation has been described in multiple individuals of Italian descent with impaired glucose tolerance or maturity-onset diabetes of the young (MODY) (Guazzini B et al. Hum. Mutat., 1998;12:136; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Mantovani V et al. Hum. Mutat., 2003 Oct;22:338). Furthermore, in a Brazilian family with MODY, this mutation co-segregated with hyperglycemia and was absent in normoglycemic family members (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.2	.;L;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.11	.;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.94
MutPred		0.83		.;Gain of methylation at E221 (P = 0.0028);.;.;.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.87
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -2

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

Other links and lift over

dbSNP: rs193922317; hg19: chr7-44189377; COSMIC: COSV60786559; COSMIC: COSV60786559;