chr7-44145176-G-C

Variant names:

• chr7-44145176-G-C
• NM_000162.5:c.1358C>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):​c.1358C>G​(p.Ser453Trp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S453S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.43

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 mutagenesis_site Increased glucokinase activity based on measure of catalytic efficiency. Increased affinity for glucose. (size 0) in uniprot entity HXK4_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-44145176-G-C is Pathogenic according to our data. Variant chr7-44145176-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2734985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1358C>G	p.Ser453Trp	missense_variant	Exon 10 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1358C>G	p.Ser453Trp	missense_variant	Exon 10 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Inactivating variants are associated with MODY type II (MIM#125851) and diabetes mellitus, permanent neonatal 1 (MIM#606176). Activating variants have been associated with hyperinsulinemic hypoglycemia, and usually cluster in a discrete region of the protein termed the allosteric activator site (PMID: 19790256). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive inheritance is rare, caused by biallelic variants resulting in a more severe and neonatal phenotype (MIM#606176) (OMIM, PMID: 19790256). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated hexokinase_2 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ser453Leu) has been reported in multiple families with MODY (ClinVar, PMID: 14517956, 18399931, 19790256) and mutagenesis and transfection to E. coli cells has shown that this variant is inactivating, with reduced enzyme activity compared to wild-type (PMID: 16731834). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two families with MODY (PMID: 19790256). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the GCK protein (p.Ser453Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (MODY) (PMID: 19790256; Invitae). In at least one individual the variant was observed to be de novo. 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%. This variant disrupts the p.Ser453 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14517956, 16731834, 18399931; Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.92
MutPred		0.94		.;.;Loss of disorder (P = 0.0034);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44184775;