7-44145212-G-C

Position:

chr7-44145212-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PP4_ModeratePP2PP3PS3_ModeratePM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1322C>G variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; PMID:25665835). 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.Ser441Trp has RAI=0.11, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 19884385). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:27420379, 25665835, 19884385, 17573900, 16965331, 11508276, internal lab contributors). In summary, 1322C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367397017/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Consequence

GCK
NM_000162.5 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 6.37

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.1322C>G	p.Ser441Trp	missense_variant	10/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.1322C>G	p.Ser441Trp	missense_variant	10/10	1	NM_000162.5	ENSP00000384247	P1	P35557-1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

Cov.:

31

GnomAD4 genome

Cov.:

33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2021	Published in vitro functional studies demonstrate greatly reduced enzyme activity compared to wildtype (Barbetti et al., 2009); Not observed 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: 19884385, 25665835, 11508276, 17573900, 14517946, 28726111, 16965331) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 12, 2019	- -

GCK-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2023

The GCK c.1322C>G variant is predicted to result in the amino acid substitution p.Ser441Trp. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (see for example, Figure 1, Massa et al. 2001. PubMed ID: 11508276; Table 1, Estalella et al. 2007. PubMed ID: 17573900; Oriola et al. 2015. PubMed ID: 25665835) and in multiple individuals with impaired fasting glucose (Figure 1, Barbetti et al. 2009. PubMed ID: 19884385; Table 2, Aloi et al. 2017. PubMed ID: 28726111). An in vitro experimental study shows this variant has greatly reduced enzyme activity compared to wildtype (Table 2, Barbetti et al. 2009. PubMed ID: 19884385). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jun 25, 2023

The c.1322C>G variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; PMID: 25665835). 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.Ser441Trp has RAI=0.11, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 19884385). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 27420379, 25665835, 19884385, 17573900, 16965331, 11508276, internal lab contributors). In summary, 1322C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3, PS4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.56

D

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

33

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

.;D;D;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Pathogenic

1.0

D;D;D;.;D;D

M_CAP

Pathogenic

0.64

D

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.6

.;.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.73

T

PROVEAN

Pathogenic

-6.8

.;D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;D;D;D;D

Vest4

0.79

MutPred

0.92

.;.;Loss of disorder (P = 5e-04);.;.;.;

MVP

0.98

MPC

2.6

ClinPred

1.0

D

GERP RS

4.9

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: chr7-44184811;