7-44151069-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.370G>A(p.Asp124Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D124H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:2
• Conservation: PhyloP100: 7.91

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 hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000162.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44151069-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 447397.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-44151069-C-T is Pathogenic according to our data. Variant chr7-44151069-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 211073.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.370G>A	p.Asp124Asn	missense_variant	4/10	ENST00000403799.8
GCK	NM_033507.3	c.373G>A	p.Asp125Asn	missense_variant	4/10
GCK	NM_033508.3	c.367G>A	p.Asp123Asn	missense_variant	5/11
GCK	NM_001354800.1	c.370G>A	p.Asp124Asn	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.370G>A	p.Asp124Asn	missense_variant	4/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251174 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461616 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp124Asn variant in GCK has been reported in at least 6 individuals (including 1 Polish, 1 Czech, 1 German, and 2 Caucasian individuals) with Monogenic Diabetes (PMID: 27106716, 22773699, 24918535, 20337973; DOI: 10.2337/db18-1509-P), and has been identified in 0.002893% (1/34564) of Latino chromosomes and 0.0008805% (1/113574) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759072800). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 211073). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP2, PP3 (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Nov 02, 2023	The c.370G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 124 (p.(Asp124Asn)) 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 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and one copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 22773699, internal lab contributors). This variant was identified in a at least three individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.379G>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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2023	Variant summary: GCK c.370G>A (p.Asp124Asn) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) 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 8e-06 in 251174 control chromosomes (gnomAD). c.370G>A has been reported in the literature in several individuals affected with Monogenic Diabetes (e.g. Osbak_2009, Pruhova_2010, Fendler_2014, Caswell_2020, Bonneford_2020, Bodis_2022, Gjesing_2022), including a family with multiple affected members (Bodis_2022), however the variant was also found in healthy control(s) (Bonneford_2020). In a recent large study evaluating UK Biobank data, the variant was found in 3/14622 diabetes cases and 10/185509 controls without diagnosis of diabetes (Billings_2022). These data indicate that the variant is likely to be associated with disease, but might also suggest a reduced penetrance. At least one publication also reported in vivo functional analysis (euglycemic-hyperinsulinemic clamp) performed in two carriers heterozygous for the D124N variant, and found impairments of insulin-secretion, with beta-cell function about 50% of the controls (Bodis_2022). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments, i.e. as VUS (n=2), likely pathogenic (n=1) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 124 of the GCK protein (p.Asp124Asn). This variant is present in population databases (rs759072800, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 19790256, 20337973, 22773699, 24918535, 32533152, 35176401, 36257325; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 211073). 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%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 19, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	Identified in multiple unrelated patients in association with MODY; however, patient-specific clinical and segregation information is limited or not provided (Pruhova et al., 2010; Chakera et al., 2012; Tracz et al., 2014); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 34662886, 19790256, 22773699, 24918535, 36208030, 20337973, 27059371, 32533152, 35176401) -

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

Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2021	The p.Asp124Asn change affects a highly conserved amino acid residue located in a hexokinase domain of the GCK protein that is known to be functional. The p.Asp124Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in the literature in other patients with GCK related MODY (PMIDs: 27106716, 20337973, 24918535, 27059371). This particular sequence change has been described in the gnomAD database in two heterozygous individuals which corresponds to a population frequency of 0.00080% (dbSNP rs759072800). This sequence change is the likely cause of this patient's phenotype, however functional studies have not been performed to prove this conclusively. -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PM2, PP3, PP1_Strong, PS4, PM5_Supporting, PP4, PP2 -

GCK-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The GCK c.370G>A variant is predicted to result in the amino acid substitution p.Asp124Asn. This variant has been reported in multiple unrelated individuals with MODY (Supp. Table S1, Osbak et al 2009. PubMed ID: 19790256; Pruhova S et al 2010. PubMed ID: 20337973; Chakera AJ et al 2012. PubMed ID: 22773699; Supplementary Table 1, Carmody D et al 2016. PubMed ID: 27106716; Caswell RC et al 2020. PubMed ID: 32533152). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic by ClinGen monogenic diabetes variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/211073/). A different substitution at the same amino acid (p.Asp124His) has also been reported in patients with MODY (Supp. Table S1 at Osbak et al. 2009. PubMed ID: 19790256). In summary, this variant is interpreted as pathogenic. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs759072800 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;.;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.73
MutPred		0.94		.;Gain of catalytic residue at D124 (P = 0.0764);.;.;
MVP		0.99
MPC		2.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.97

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: rs759072800; hg19: chr7-44190668;