rs587780343

chr7-44145638-C-Achr7-44145638-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.1112G>T(p.Cys371Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C371R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.93

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 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr7-44145639-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2578362.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-44145638-C-A is Pathogenic according to our data. Variant chr7-44145638-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 129140.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.1112G>T	p.Cys371Phe	missense_variant	9/10	ENST00000403799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.1112G>T	p.Cys371Phe	missense_variant	9/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 09, 2023

The c.1112G>T variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to phenylalanine at codon 371 (p.(Cys371Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.931, 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 hyperglycemia (PS4; PMID 24735133, internal lab contributors). This variant segregated with hyperglycemia with 12 informative meioses in 3 families with MODY (PP1_Strong; 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% as well as either OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PP1_Strong, PS4, PP4_Moderate . -

Gestational diabetes Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 23, 2020

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1112G>T, in exon 9 that results in an amino acid change, p.Cys371Phe. The p.Cys371Phe change affects a highly conserved amino acid residue located in a Hexokinase domain of the GCK protein that is known to be functional. The p.Cys371Phe substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in two families with MODY (PMID: 19790256). This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs587780343). Different sequence changes affecting the same amino acid residue (p.Cys371Arg, p.Cys371Trp, p.Cys371Trp) have also been described in patients with GCK-related MODY (PMID: 19790256) -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 129140). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 24735133; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 371 of the GCK protein (p.Cys371Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.94
MutPred		0.97		.;.;Loss of disorder (P = 0.1014);.;.;.;
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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

Other links and lift over

dbSNP: rs587780343; hg19: chr7-44185237;