7-44147726-A-G

Position:

chr7-44147726-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000162.5(GCK):c.787T>C(p.Ser263Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.326

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 12 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000162.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-44147726-A-G is Pathogenic according to our data. Variant chr7-44147726-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.787T>C	p.Ser263Pro	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3 linkuse as main transcript	n.76A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.787T>C	p.Ser263Pro	missense_variant	7/10	1	NM_000162.5	P1	P35557-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461152

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726904

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 263 of the GCK protein (p.Ser263Pro). This variant is present in population databases (rs193922331, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 12442280, 25306193, 25555642, 32074423; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36258). 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%. Experimental studies have shown that this missense change affects GCK function (PMID: 21921030, 22028181, 22820548). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2022	Published functional studies demonstrate protein misfolding causing thermal instability, cellular dimerization/aggregation, enhanced degradation rates, and decreased activity compared to wildtype (Negahdar et al., 2012; Zelent et al., 2011; Cullen et al., 2011); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21831042, 21921030, 22028181, 12442280, 15305805, 16731834, 32041611, 22820548) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 14, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected the stability and activity of the protein (PMID: 22820548, 22028181, 21921030). -

Maturity-onset diabetes of the young type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Jun 09, 2017	The c.787T>C variant in codon 263 (exon 7) of the glucokinase gene, GCK, results in the substitution of Serine to a Proline. The c.787T>C was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported to segregate with diabetes in a family whose clinical picture is consistent with Maturity-Onset Diabetes of the Young (MODY) (12442280). Functional analyses of this variant have demonstrated thermal instability, protein misfolding and aberrant dimerization (22820548;16731834). Additionally, multiple lines of computational evidence (SIFT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PS3, PM2, PP1, PP3 -

Maturity onset diabetes mellitus in young

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2019	The p.Ser262Pro variant in GCK has been reported in at least 3 individuals with suspicion for MODY and segregated with disease in at least 3 affected members of two families (Cao 2002, Sagen 2006, GeneDx personal communication). It has also been identified in 1/128844 European chromosomes by gnomAD (http://gnomad.broad institute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 36258). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. However, multiple in vitro functional studies suggest that this variant impacts protein function (Sag en 2006, Zelent 2011, Fenner 2011, Negahdar 2012, George 2014). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Ser262Pro variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PS4_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2018	The p.S263P variant (also known as c.787T>C), located in coding exon 7 of the GCK gene, results from a T to C substitution at nucleotide position 787. The serine at codon 263 is replaced by proline, an amino acid with similar properties. This variant was identified in two maturity-onset diabetes of the young families (Cao H et al. Hum. Mutat., 2002 Dec;20:478-9; Sagen JV et al. Diabetes, 2006 Jun;55:1713-22). When stably over expressed in HEK293 cells and MIN6 cells, this variant generated a misfolded protein with an increased rate of degradation and a propensity to self-associate and form dimers and aggregates (Negahdar M et al. Biochim. Biophys. Acta, 2012 Nov;1822:1705-15). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 05, 2022

The heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the exon 7 of GCK gene has been reported in multiple patients with hyperglycemia and found to be co-segregated with disease phenotype [PMID: 22820548, 16731834, 32074423] and was reported as pathogenic in a cohort study involving hypertriglyceridemia and familial hypercholesterolemia patients [PMID: 32041611]. In vitro functional studies demonstrated that p. Ser263Pro variant leads to protein misfolding, thermal instability and aberrant dimerization [PMID:22820548,16731834]. The variant has 0.000006570 allele frequency in the gnomAD(v3) database (1 out of 152218 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The identified variant has been reported in the ClinVar database as a Likely Pathogenic [Variation ID: 36258]. The variant affects a moderately conserved residue in the large hexokinase domain of the GCK protein [PMID: 31638168] and is predicted deleterious by multiple in silico tools (CADD score = 22.7, REVEL score = 0.689). Based on the available evidence, the heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the GCK gene is classified as ‘Likely Pathogenic’. -

Gestational diabetes

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 18, 2021

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.787T>C, in exon 7 that results in an amino acid change, p.Ser263Pro. The p.Ser263Pro change affects a poorly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser263Pro substitution. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0032% % (dbSNP rs193922331). This sequence change has been previously reported in patients with GCK-related hyperglycemia (PMIDs: 12442280, 16731834). Functional studies have also demonstrated that p.Ser263ro sequence change results in reduced protein misfolding and aberrant dimerization (PMIDs: 22820548, 16731834). These collective evidences indicate that this sequence change is the likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;D;.;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.92

D;D;.;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.5

.;L;.;.;.

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.7

.;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.048

B;B;B;B;.

Vest4

0.47

MutPred

0.79

.;Loss of glycosylation at S263 (P = 0.0429);.;.;.;

MVP

0.91

MPC

1.4

ClinPred

0.86

GERP RS

-0.043

Varity_R

0.90

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over