7-44153381-C-T

Position:

• chr7-44153381-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4 PP1_Moderate PM5_Supporting PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.128G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 43 (p.(Arg43His)) 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 0.8159, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated that the p.Arg43His variant has normal relative activity index (RAI>0.5) and normal GKA/GKRP interaction; however the relative stability index (RSI) was not calculated and therefore neither PS3 or BS3 can be applied (PMID:22611063). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 11942313, 22611063, 27106716, 25015100, 22493702, 30245511, 31638168, 33046911). 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 OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:30245511). This variant segregated with diabetes/hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 22611063, 22493702). Another missense variant, c.127C>T (p.Arg43Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg43His (PM5_Supporting). In summary, the c.128G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified for by the GlinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239718/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 4.14

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.

• 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.128G>A	p.Arg43His	missense_variant	2/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.131G>A	p.Arg44His	missense_variant	2/10		NP_277042.1
GCK	NM_033508.3	c.125G>A	p.Arg42His	missense_variant	3/11		NP_277043.1
GCK	NM_001354800.1	c.128G>A	p.Arg43His	missense_variant	2/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.128G>A	p.Arg43His	missense_variant	2/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251444 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Aug 25, 2023	The c.128G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 43 (p.(Arg43His)) 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 0.8159, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated that the p.Arg43His variant has normal relative activity index (RAI>0.5) and normal GKA/GKRP interaction; however the relative stability index (RSI) was not calculated and therefore neither PS3 or BS3 can be applied (PMID: 22611063). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 11942313, 22611063, 27106716, 25015100, 22493702, 30245511, 31638168, 33046911). 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 OGTT increment < 3 mmol/L) (PP4_Moderate; PMID: 30245511). This variant segregated with diabetes/hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 22611063, 22493702). Another missense variant, c.127C>T (p.Arg43Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg43His (PM5_Supporting). In summary, the c.128G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified for by the GlinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Jul 22, 2016	The c.128G>A variant in codon 43 (exon 2) of the glucokinase gene, GCK, results in the substitution of Arginine to Histidine. This variant has been reported in the literature in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (22611063, 22493702, 11942313), with evidence of co-segregation with diabetes in two separate families (22611063, 22493702). Different amino acid substitutions at this residue, Arg43Ser and Arg43Cys, have also been reported in patients with MODY2 (17573900, 19358091, 25015100). Functional studies suggest that the Arg43His and Arg43Cys substitutions result proteins with decreased stability compared to wild-type (22611063, 25015100). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS3, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2023	Variant summary: GCK c.128G>A (p.Arg43His) results in a non-conservative amino acid change located in the 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 allele was found at a frequency of 4e-06 in 251444 control chromosomes (gnomAD). The variant, c.128G>A, has been reported in the literature in multiple individuals affected with Monogenic Diabetes, including families where the variant segregated with the disease (e.g. Ziemssen_2002, Beer_2012, Valentinova_2012, Huang_2018, Glotov_2019, Abreu_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that while the R43H variant protein exhibited near normal enzyme kinetics, it had decreased thermostability compared to the wild-type (Beer_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11942313, 22611063, 22493702, 30155490, 31638168, 35592779). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg43His variant in GCK has been reported in at least 8 individuals (including 1 German, 1 Slovakian, 1 Swiss, 1 Cyproit, and 1 Hispanic individuals) with Monogenic Diabetes, segregated with disease in 6 affected relatives from 2 family (PMID: 11942313, 24430320, 11942313, 22611063, 22493702, 27106716; DOI:10.3252/pso.eu.54espe.2015; Shammas et al. 2012), and has been identified in 0.002891% (1/34592) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764232985). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 393453). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg43Cys, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 21348868, 30592380, 21521320, 23771172, 19790256, 25015100/Variation ID: 585911). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM5, PM2_Supporting, PP3, PP1_moderate (Richards 2015). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 43 of the GCK protein (p.Arg43His). This variant is present in population databases (rs764232985, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of autosomal dominant maturity onset diabetes of the young (PMID: 11942313, 22493702, 22611063, 28726111, 30155490, 30245511, 31638168, 33046911, 34108472; Invitae). ClinVar contains an entry for this variant (Variation ID: 393453). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GCK function (PMID: 22611063). This variant disrupts the p.Arg43 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17573900, 22611063, 23771172). 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	GeneDx	Sep 28, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 25015100, 11942313, 22611063, 19790256, 17573900, 19358091, 27106716, 30245511, 24430320, 31638168, 22493702, 31291970, 34108472, 33277730, 32375122, 33046911, 35472491, 35592779, 36208030) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. While thermostability assays reportedly showed that this variant’s GCK activity was statistically decreased, it was at fairly high temperatures and it is uncertain how that would translate in vivo (PMID 22611063). -

Maturity onset diabetes mellitus in young Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2023	The p.R43H variant (also known as c.128G>A), located in coding exon 2 of the GCK gene, results from a G to A substitution at nucleotide position 128. The arginine at codon 43 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in multiple individuals with a maturity-onset diabetes of the young phenotype (Ziemssen F et al. Diabetologia, 2002 Feb;45:286-7; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541; Ma Y et al. Genet. Med., 2019 04;21:939-947), including in one family with 3 individuals with this variant (Steele AM et al. JAMA, 2014 Jan;311:279-86). Functional studies demonstrated that protein with this variant is unstable with decreased thermostability compared to wild type (Beer NL et al. Diabetes Care, 2012 Jul;35:1482-4). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Arg42His (also known as p.Arg43His) variant in GCK has been reported in at least 11 individuals with maturity onset diabetes of the young (MODY) and segregated with disease in at least 4 affected individuals from 2 families (Carmody 2016 PMID: 27106716, Beer 2012 PMID: 22611063, Steele 2014 PMID: 24430320, Valentínová, 2012 PMID: 22493702, Ziemssen 2002 PMID: 11942313, Ozbak 2009 PMID: 19790256, Glotov 2019 PMID: 31638168, Ma 2019 PMID: 30245511). It has also been identified in 0.003% (1/34592) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 393453). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, in vitro functional studies provide some evidence that this variant impacts protein function (Beer 2012 PMID: 22611063); however, these types of assays may not accurately represent biological function. Additional variants, resulting in different amino acid changes at the same position (e.g., p.Arg43Cys, p.Arg43Ser) has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PP1, PP3, PS3_Supporting. -

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

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PS4, PP1_Moderate, PP2, PP3, PM2, PM5, PP4, PS3 -

GCK-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2022

The GCK c.128G>A variant is predicted to result in the amino acid substitution p.Arg43His. This variant has been reported in the heterozygous state in multiple individuals with diabetes and maturity onset diabetes of the young (MODY) (Ziemssen et al. 2002. PubMed ID: 11942313; Beer et al. 2012. PubMed ID: 22611063; Glotov et al. 2019. PubMed ID: 31638168; Bonneford et al. 2020. PubMed ID: 33046911, supplementary tables; Ma et al. 2019. PubMed ID: 30245511; Steele et al. PubMed ID: 24430320, supplementary tables; Valentinova et al. 2012. PubMed ID: 22493702; Carmody et al. 2016. PubMed ID: 27106716, supplementary tables). Both functional and family segregation studies have supported its pathogenicity (Beer et al. 2012. PubMed ID: 22611063). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-44192980-C-T). Multiple other variants at this same amino acid position have also been reported in the heterozygous state in individuals with MODY (p.Arg43Ser, p.Arg43Gly, p.Arg43Cys, p.Arg43Pro; Human Gene Mutation Database, https://www.hgmd.cf.ac.uk/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T;.;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	.;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.034	.;D;D;D;D
Sift4G	Uncertain	0.056	T;T;T;D;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.88
MutPred		0.94		.;Loss of MoRF binding (P = 0.037);.;.;Loss of MoRF binding (P = 0.037);
MVP		0.97
MPC		2.5
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.79
gMVP		0.92

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: rs764232985; hg19: chr7-44192980;