rs104894008

chr7-44147732-C-Gchr7-44147732-C-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.781G>C(p.Gly261Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G261E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• 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 26 ACMG points.

• PS1: Transcript NM_000162.5 (GCK) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 16135
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr7-44147731-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2578353.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-44147732-C-G is Pathogenic according to our data. Variant chr7-44147732-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 447418.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.781G>C	p.Gly261Arg	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.82C>G		non_coding_transcript_exon_variant	1/3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (PMID: 1502186, 30592380, 31291970, 36227502). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447418). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2016	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 12, 2023

The c.781G>C 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 was identified in an individual 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 hyperglycemia with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). The nucleotide change c.781G>A, which causes the same amino acid change, has been classified as pathogenic by the ClinGen MDEP (PS1). 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, the c.781G>C 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 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS3_Moderate, PS1, PS4_Moderate, PP4_Moderate. -

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	31
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	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
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)		0.0		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: rs104894008; hg19: chr7-44187331;