7-44147732-C-T

Position:

• chr7-44147732-C-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PM3 PP1_Strong PP2 PP3 PP4_Moderate PS4 PS2 PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two 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) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID:19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA126211/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:10
• Conservation: PhyloP100: 7.83

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 21 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.781G>A	p.Gly261Arg	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.82C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.781G>A	p.Gly261Arg	missense_variant	7/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251056 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461202 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 1992	- -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PM2, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 30, 2021	The GCK c.781G>A variant is classified as Likely Pathogenic (PS3, PM2, PP3) The GCK c.781G>A variant is a single nucleotide change in exon 7/10 of the GCK gene, which is predicted to change the amino acid glycine at position 261 in the protein to arginine. This variant is absent from population databases (PM2). Well-established functional studies show a deleterious effect of this variant ( Gidh-Jain et al. (PMID:8446612) ) (PS3). Please note this variant has been previously reported in the literature as: NM_0001354800.1: c.781G>A, p.Gly261Arg. -
Pathogenic, criteria provided, single submitter	clinical testing	Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile	Apr 01, 2019	Using next-generation sequencing, we found the heterozygous variant in a patient under suspect of MODY. -Mean coverage: 122X; 98.4% of target-regions at 20X -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	Published functional studies demonstrate a damaging effect with the presence of the variant causing significantly decreased Glucokinase activity in comparison to wild-type (Gidh-Jain et al., 1993; Raimondo et al., 2014); 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 often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 9049484, 30191644, 21521320, 22611063, 10525657, 25015100, 8446612, 1502186, 17573900, 27167055, 1464666, 10694920, 30663027, 21518409, 22761713, 8168652, 19903754, 34440516, 34496959) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2022	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Heterozygous individuals with this variant presented with clinical features of MODY, while homozygous individuals presented with permanent neonatal diabetes mellitus. This variant associates with MODY in multiple families. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in reduced kinase activity (PMID: 8446612, 19903754, 10525657). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 261 of the GCK protein (p.Gly261Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant GCK-related conditions (PMID: 1502186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16135). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 10525657). For these reasons, this variant has been classified as Pathogenic. -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2020

The p.G261R pathogenic mutation (also known as c.781G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 781. The glycine at codon 261 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families with a clinical diagnosis of maturity-onset diabetes of the young (MODY), and has been shown to segregate with disease (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Yorifuji T et al. Pediatr Diabetes, 2012 Feb;13:26-32). In one family, the proband was homozygous for p.G261R and presented with permanent neonatal diabetes mellitus; elevated fasting glucose was detected in four heterozygous family members: two sisters, the father with a history of diabetes, and the mother with a history of gestational diabetes (Bennett K et al. Pediatr Diabetes, 2011 May;12:192-6). In addition, functional studies have shown that p.G261R mutant GCK has significantly reduced enzymatic activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Beer NL et al. Diabetes Care, 2012 Jul;35:1482-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 12, 2023

The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two 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) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2. -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.94		.;Loss of glycosylation at S263 (P = 0.0679);.;.;.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894008; hg19: chr7-44187331;