rs1375656631

Positions:

chr7-44147738-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4PP1_StrongPM5_SupportingPP4_ModeratePP2PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and 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). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). 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 a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367400584/MONDO:0015967/086

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GCK
ENST00000403799.8 missense

Scores

14

3

2

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 7.83

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:

LOC105375258 (HGNC:):

LOC105375258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS4

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

PM2

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

PM5

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

PP1

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.775G>A	p.Ala259Thr	missense_variant	7/10	ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3 linkuse as main transcript	n.88C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.775G>A	p.Ala259Thr	missense_variant	7/10	1	NM_000162.5	ENSP00000384247	P1	P35557-1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251056

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461214

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

726938

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Aug 12, 2023	The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and 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). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). 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 a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2022	Variant summary: GCK c.775G>A (p.Ala259Thr) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251106 control chromosomes. c.775G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes, specifically features of Maturity Onset Diabetes of the Young (MODY2) (example, Hattersley_1998, Matyka_1998, Thomson_2003, Lukasova_208, Capuano_2012, Tatsi_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 435302). This missense change has been observed in individuals with clinical features of autosomal dominant maturity onset diabetes of the young (PMID: 9713013, 22761713, 25414397, 26287533, 31638168; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 259 of the GCK protein (p.Ala259Thr). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 14517956, 25414397, 18271687, 34956103, 29056535, 26875109, 31604004, 9662401, 26287533, 29927023, 9713013, 22761713, 31638168, Sangwoo-2022[Article], 34101350, 35029855) -

Maturity-onset diabetes of the young type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.46

D

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

30

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

.;D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Pathogenic

0.84

D

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.6

.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.47

T

PROVEAN

Uncertain

-3.5

.;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.90

P;P;P;P;.

Vest4

0.94

MutPred

0.94

.;Loss of stability (P = 0.0611);.;.;.;

MVP

0.98

MPC

1.8

ClinPred

0.99

D

GERP RS

5.2

Varity_R

0.92

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1375656631; hg19: chr7-44187337; COSMIC: COSV60787622; COSMIC: COSV60787622;