7-44147747-C-T

Position:

chr7-44147747-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000162.5(GCK):c.766G>A(p.Glu256Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E256D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.83

Variant links:

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 links:

LOC105375258 (HGNC:):

LOC105375258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000162.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-44147747-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 7-44147747-C-T is Pathogenic according to our data. Variant chr7-44147747-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44147747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3 linkuse as main transcript	n.97C>T		splice_region_variant, non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	7/10	1	NM_000162.5	P1	P35557-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251142

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461244

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726958

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the GCK protein (p.Glu256Lys). This variant is present in population databases (rs769268803, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 17573900, 27634015, 28331372, 31957151). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265175). 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 expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 8446612). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with MODY. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 18397317. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2021	Published functional studies show markedly reduced glucokinase activity compared to wildtype and demonstrates a hypomorphic allele (Gidh-Jain et al., 1993; Molnes et al., 2008); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 31957151, 25555642, 23476789, 23624530, 20337973, 17573900, 27913849, 26123671, 18397317, 25306193, 23778137, 27634015, 28331372, 8446612) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The c.766G>A variant in exon 7 of the GCK gene substitutes the glutamic acid with lysine at amino acid position 256 of the glucokinase protein. This is a recurrent pathogenic variant that has been reported in the heterozygous state in several individuals with MODY. It is not a common variant in the general population (observed in 1 of 251,142 alleles; GnomAD v2.1). The p.Glu256Lys variant falls within the glucose binding site of GCK and has been experimentally demonstrated to cause a loss of catalytic activity. PMIDs: 25555642, 27634015, 28331372, 23476789, 8446612, NBK500456, 30225972, 21844708, 23771172 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	The GCK c.766G>A; p.Glu256Lys variant (rs769268803) is reported in the literature in multiple patients with maturity-onset diabetes of the young, type II (MODY2) and non-insulin-dependent diabetes (NIDDM), although no clear co-segregation is shown (Brahm 2016, Emelyanov 2017, Mirshahi 2022, Xu 2020). This variant is also reported in ClinVar (Variation ID: 265175) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Multiple lines of conformational and functional studies showed that this variant is part of the critical glucose binding domain (Yellapu 2013) and has profound impact on GCK catalytic activity ex vivo (Gidh-Jain 1993). Different amino acid substitutions at this residue (p.Glu256Ala, p.Glu256Asp, and p.Glu256Gly) have also been reported in patients with MODY2 and are considered to be disease-causing (Santana 2017, Garin 2008, Zmyslowska 2022). The glutamic acid at codon 256 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.977). Based on available information, the p.Glu256Lys variant is considered to be pathogenic. References: Brahm AJ et al. Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. Can J Diabetes. 2016 Dec;40(6):555-560. PMID: 27634015. Garin I, et al. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf). 2008 Jun;68(6):873-8. PMID: 18248649. Gidh-Jain M, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID: 8446612. Emelyanov AO et al. A glucokinase gene mutation in a young boy with diabetes mellitus, hyperinsulinemia, and insulin resistance. Int Med Case Rep J. 2017 Mar 7;10:77-80. PMID: 28331372. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Santana LS et al. Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. Clin Genet. 2017 Oct;92(4):388-396. PMID: 28170077. Xu A et al. Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. Pediatr Diabetes. 2020 May;21(3):431-440. PMID: 31957151. Yellapu NK et al. Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study. Biotechnol Res Int. 2013;2013:264793. PMID: 23476789. Zmyslowska A et al. Next- generation sequencing is an effective method for diagnosing patients with different forms of monogenic diabetes. Diabetes Res Clin Pract. 2022 Jan;183:109154. PMID: 34826540. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1833104:Permanent neonatal diabetes mellitus;C1865290:Hyperinsulinism due to glucokinase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Maturity-onset diabetes of the young type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 22, 2024

Criteria applied: PS3,PS4,PM5,PM2_SUP,PP1,PP3 -

Maturity onset diabetes mellitus in young

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2019

The p.E256K pathogenic mutation (also known as c.766G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 766. The glutamic acid at codon 256 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in multiple individuals and families with maturity-onset diabetes of the young (MODY) (Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Irgens HU et al. Diabetologia, 2013 Jul;56:1512-9). Based on structural analysis, this variant is anticipated to disrupt glucose binding, resulting in reduced activity (Pilkis SJ et al. J. Biol. Chem., 1994 Sep;269:21925-8; Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Yellapu NK et al. Biotechnol Res Int, 2013 Feb;2013:264793). Functional studies have illustrated this, by showing that E256K mutant protein has significantly reduced enzymatic activity (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Molnes J et al. FEBS J., 2008 May;275:2467-81). In addition, another alteration at the same codon, p.E256D, has been reported to cause MODY (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). Based on the supporting evidence, p.E256K is interpreted as a disease-causing mutation. -

Monogenic diabetes

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 08, 2024

Variant summary: GCK c.766G>A (p.Glu256Lys) results in a 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 allele was found at a frequency of 4e-06 in 251142 control chromosomes (gnomAD). c.766G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (examples: Wajngot_1994, Estalella_2007 Brahm_2016, Emelyanov_2017, Colclough_2022) and at-least has been reported as a de novo occurrence (Emelyanov_2017). At least one publication reports experimental evidence that this variant impairs normal protein activity (Gidh-Jain_1993). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8446612, 17573900, 28331372, 27634015, 34789499, 7958490). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;.;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

1.0

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.99

MutPred

0.98

.;Gain of ubiquitination at E256 (P = 0.0203);.;.;.;

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

5.2

Varity_R

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over