chr7-44150004-C-T

Position:

• chr7-44150004-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000162.5(GCK):​c.544G>A​(p.Val182Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V182L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.91

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 16 ACMG points.

• PM1: In a region_of_interest Hexokinase small subdomain (size 136) in uniprot entity HXK4_HUMAN there are 46 pathogenic changes around while only 2 benign (96%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 7-44150004-C-T is Pathogenic according to our data. Variant chr7-44150004-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 129144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44150004-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.544G>A	p.Val182Met	missense_variant	5/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.547G>A	p.Val183Met	missense_variant	5/10		NP_277042.1
GCK	NM_033508.3	c.541G>A	p.Val181Met	missense_variant	6/11		NP_277043.1
GCK	NM_001354800.1	c.544G>A	p.Val182Met	missense_variant	5/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.544G>A	p.Val182Met	missense_variant	5/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461660 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The c.544G>A (p.Val182Met, rs587780345) variant, located in exon 5 of the GCK gene, results in substitution of methionine for valine at amino acid position 182 of the protein. This variant has been reported as pathogenic in the literature and in ClinVar by multiple submitters (PMID: 8433729, 23771172, 30191644). Functional characterization has shown that this variant results in loss of glucokinase activity (PMID: 10525657). This variant is absent from large population controls (0 of >250,000 alleles tested; Genome Aggregation Database v2.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10525657) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 182 of the GCK protein (p.Val182Met). 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: 8433729, 23771172, 30191644). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 129144). 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, 10525657). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 8446612, 19790256, 23771172, 29510678, 33852230, 31957151, 31968686, 29056535, 29284910, 25695774, 15102714, 14517956, 21395678, 25494859, 8433729, 20337973, 30191644, 33046911, 32792356, 33878173, 36208030, 18056790, 25306193, 25555642, 35177841, 25082184, 10525657) -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 20, 2018	- -

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

Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val182Met variant in GCK has been reported in at least 9 individuals with maturity-onset diabetes of the young (MODY) type 2, segregated with disease in 4 affected relatives from 2 families (PMID: 29510678, 20337973, 21395678, 25082184, 23771172, 25306193, 25494859), and was absent from large population studies. Animal models in mice have shown that this variant causes MODY type 2 (15102714, 18056790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for MODY type 2 in an autosomal dominant manner based on the phenotype of mouse models being consistent with human disease, the increased prevalence of the variant in affected individuals, including relatives, compared to controls, and computational evidence. ACMG/AMP Criteria applied: PS3_PM2, PS4_moderate, PP3, PP1 (Richards 2015). -

Maturity onset diabetes mellitus in young Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Val181Met (also known as p.Val182Met) variant in GCK has been reported in >7 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in >2 relatives (Froguel 1993 PMID: 8433729; Pruhova 2010 PMID: 20337973; McDonald 2011 PMID: 21395678; Ellard 2013 PMID: 23771172; Alkorta-Aranburu 2014 PMID: 25306193; Carmody 2015 PMID: 25494859; Gandica 2015 PMID: 25082184; Li 2018 PMID: 29510678). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 129144) and was absent from large population studies. Animal models in mice have shown that this variant causes MODY (Davis 1999 PMID: 10525657; Inoue 2014 PMID: 15102714; Aigner 2018 PMID: 18056790) and computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PS3, PP3, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2023	The p.V182M pathogenic mutation (also known as c.544G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 544. The valine at codon 182 is replaced by methionine, an amino acid with highly similar properties. This mutation was first reported to co-segregate with disease in two French MODY families (Froguel P et al. N. Engl. J. Med., 1993 Mar;328:697-702) and has subsequently been reported in multiple additional families (Costa A et al. Eur. J. Endocrinol., 2000 Apr;142:380-6; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Carmody D et al. Diabet. Med., 2015 Jun;32:e20-3). In addition, when expressed in E. coli and purified, mutant glucokinase carrying this mutation showed significantly decreased enzyme activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Davis EA et al. Diabetologia 1999 Oct;42(10):1175-86). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

- -

Gestational diabetes Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 11, 2020

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.544G>A, in exon 5 that results in an amino acid change, p.Val182Met. This sequence change has been previously described in several patients with GCK-related MODY (PMIDs: 8433729, 20337973, 23771172, 25494859 and 25555642). This sequence change is absent from the large population databases such as ExAC and gnoMAD (dbSNP rs587780345). The p.Val182Met change affects a highly conserved amino acid residue located in a domain of the GCK protein which is known to be functional (PMID: 8446612). The p.Val182Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.96
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587780345; hg19: chr7-44189603;