chr7-44149976-C-T

Position:

• chr7-44149976-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4 PP1_Strong PM5_Supporting PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) 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 0.873, 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 39 unrelated individuals with hyperglycemia (PS4; PMID:30259503, 29927023, 29510678, 29207974, 29056535, 27256595, 25953829, 25555642, 24918535, 20337973, 19309449, 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 13 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Another missense variant, c.571C>T p.(Arg191Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg191Gln) (PM5_Supporting). In summary, c.572G>A 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): PP3, PP2, PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10604473/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 6.17

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 14 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.
• 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.
• 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.572G>A	p.Arg191Gln	missense_variant	5/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.572G>A	p.Arg191Gln	missense_variant	5/10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the GCK protein (p.Arg191Gln). 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: 16444761, 27256595, 29510678, 30259503). ClinVar contains an entry for this variant (Variation ID: 283358). 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%. This variant disrupts the p.Arg191 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23295292, 27269892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2019	Not found in the total gnomAD dataset, and the data is high quality. This variant has been found in multiple unrelated patients that meet standard diagnostic criteria for the relevant disease. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 25555642, 33852230, 11508276, 27256595, 24918535, 20337973, 19790256, 22060211, 16444761, 19309449, 24804978, 29510678, 29056535, 29207974, 31957151, 38054414, 34373539, 35228227, 36504295, 36257325, 35472491) -

Monogenic diabetes Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Apr 19, 2024	The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) 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 0.873, 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 39 unrelated individuals with hyperglycemia (PS4; PMID: 30259503, 29927023, 29510678, 29207974, 29056535, 27256595, 25953829, 25555642, 24918535, 20337973, 19309449, 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 13 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Another missense variant, c.571C>T p.(Arg191Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg191Gln) (PM5_Supporting). In summary, c.572G>A 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): PP3, PP2, PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2022	Variant summary: GCK c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) 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 251110 control chromosomes (gnomAD). c.572G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes and the variant seggregated with the disease (example: Pruhova_2010, Codner_2009, Codner_2006, and Massa_2001). Another two variants affecting the same amino acid residue (p.R191L, p.R191W) are associated with MODY in HGMD. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PP3, PP2, PM2, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The p.R191Q pathogenic mutation (also known as c.572G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described in the heterozygous state in several unrelated individuals with maturity-onset diabetes of the young (MODY), type 2 (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Codner E et al. Pediatr Diabetes, 2009 Sep;10:382-8; Codner E et al. Diabetes Metab Res Rev;22:348-55; Fulcoli FG et al. Nat Commun, 2016 06;7:11688; Aykut A et al. Gene, 2018 Jan;641:186-189; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Li X et al. BMC Pediatr, 2018 03;18:101; Al-Kandari H et al. Sci Rep, 2021 08;11:16060). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of maturity-onset diabetes of the young (MODY), type 2 and permanent neonatal diabetes; however, its clinical significance for GCK-related neonatal hyperinsulinemic hypoglycemia is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	.;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.92
MutPred		0.92		.;Loss of MoRF binding (P = 0.1007);.;.;.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886042610; hg19: chr7-44189575; COSMIC: COSV60786052; COSMIC: COSV60786052;