Hyperinsulinemic hypoglycemia, familial, 3

Summary

Hyperinsulinemic hypoglycemia, familial, 3 (MONDO:0011236) is a disease caused by GCK (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GCK (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 148
• Phenotypes (HPO): 13

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000825	Hyperinsulinemic hypoglycemia	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0001988	Recurrent hypoglycemia	Very frequent (80-99%)
HP:0008283	Fasting hyperinsulinemia	Very frequent (80-99%)
HP:0030794	Abnormal C-peptide level	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002378	Hand tremor	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0001259	Coma	Occasional (5-29%)
HP:0005978	Type II diabetes mellitus	Occasional (5-29%)
HP:0002270	Abnormality of the autonomic nervous system	Very rare (<1-4%)
HP:0012638	Abnormality of nervous system physiology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinemic hypoglycemia, familial, 3
Mondo ID	MONDO:0011236
MeSH	C538374
OMIM	602485
Orphanet	79299
DOID	DOID:0070216
SNOMED CT	717182006
UMLS	C1865290
MedGen	355435
GARD	0002818
Is cancer (heuristic)	no

Also known as: congenital glucokinase-related hyperinsulinism · GCK-related hyperinsulinism · glucokinase-related hyperinsulinemic hypoglycemia · HHF3 · hyperinsulinemic hypoglycemia familial 3 · hyperinsulinemic hypoglycemia, familial, 3 · hyperinsulinemic hypoglycemia, familial, type 3

Data availability: 148 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › pyruvate metabolism disorder › disorder of glycolysis › hyperinsulinemic hypoglycemia, familial, 3

Related subtypes (15): glycogen storage disease VII, non-spherocytic hemolytic anemia due to hexokinase deficiency, lactic aciduria due to D-lactic acid, glycogen storage disease due to phosphoglycerate mutase deficiency, pyruvate kinase deficiency of red cells, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, Charcot-Marie-Tooth disease type 4G, glycogen storage disease due to aldolase A deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, hemolytic anemia due to glucophosphate isomerase deficiency, glycogen storage disease due to lactate dehydrogenase H-subunit deficiency, triosephosphate isomerase deficiency, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

148 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 34 conflicting classifications of pathogenicity, 25 pathogenic, 24 benign/likely benign, 10 likely pathogenic, 8 benign, 4 likely benign, 4 pathogenic/likely pathogenic, 3 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172896	NM_000162.5(GCK):c.660C>A (p.Cys220Ter)	GCK	Pathogenic	reviewed by expert panel
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	GCK	Pathogenic	reviewed by expert panel
16134	NM_000162.5(GCK):c.683C>T (p.Thr228Met)	GCK	Pathogenic	reviewed by expert panel
16140	NM_000162.5(GCK):c.1363G>A (p.Val455Met)	GCK	Pathogenic	criteria provided, single submitter
16143	NM_000162.5(GCK):c.1367C>T (p.Ala456Val)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
16144	NM_000162.5(GCK):c.641A>G (p.Tyr214Cys)	GCK	Pathogenic	criteria provided, single submitter
16146	NM_000162.5(GCK):c.271G>Y (p.Val91Leu)	GCK	Pathogenic	no assertion criteria provided
236014	NM_000162.5(GCK):c.1148C>T (p.Ser383Leu)	GCK	Pathogenic	reviewed by expert panel
2500039	NM_000162.5(GCK):c.232G>T (p.Asp78Tyr)	GCK	Pathogenic	reviewed by expert panel
265175	NM_000162.5(GCK):c.766G>A (p.Glu256Lys)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
3233994	NM_000162.5(GCK):c.1234G>A (p.Val412Met)	GCK	Pathogenic	reviewed by expert panel
3382762	NM_000162.5(GCK):c.800dup (p.Asp267fs)	GCK	Pathogenic	criteria provided, single submitter
36200	NM_000162.5(GCK):c.1358C>T (p.Ser453Leu)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36243	NM_000162.5(GCK):c.676G>A (p.Val226Met)	GCK	Pathogenic	reviewed by expert panel
36263	NM_000162.5(GCK):c.871A>T (p.Lys291Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
393451	NM_000162.5(GCK):c.748C>T (p.Arg250Cys)	GCK	Pathogenic	reviewed by expert panel
419624	NM_000162.5(GCK):c.184G>A (p.Val62Met)	GCK	Pathogenic	reviewed by expert panel
426122	NM_000162.5(GCK):c.571C>T (p.Arg191Trp)	GCK	Pathogenic	reviewed by expert panel
429500	NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435300	NM_000162.5(GCK):c.1165G>C (p.Val389Leu)	GCK	Pathogenic	criteria provided, single submitter
435306	NM_000162.5(GCK):c.667G>A (p.Gly223Ser)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
447402	NM_000162.5(GCK):c.469G>A (p.Glu157Lys)	GCK	Pathogenic	reviewed by expert panel
447419	NM_000162.5(GCK):c.793G>A (p.Glu265Lys)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
503699	NM_000162.5(GCK):c.1155del (p.Leu386fs)	GCK	Pathogenic	reviewed by expert panel
585911	NM_000162.5(GCK):c.127C>T (p.Arg43Cys)	GCK	Pathogenic	reviewed by expert panel
585923	NM_000162.5(GCK):c.608T>C (p.Val203Ala)	GCK	Pathogenic	reviewed by expert panel
585928	NM_000162.5(GCK):c.863+1G>A	GCK	Pathogenic	reviewed by expert panel
76898	NM_000162.5(GCK):c.130G>A (p.Gly44Ser)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804852	NM_000162.5(GCK):c.629T>C (p.Met210Thr)	GCK	Pathogenic	reviewed by expert panel
16138	NM_000162.5(GCK):c.391T>C (p.Ser131Pro)	GCK	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GCK	Definitive	Autosomal dominant	hyperinsulinemic hypoglycemia, familial, 3	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCK	2,245

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	11420.0×	5e-04	GCK
Regulation of gene expression in beta cells	1	519.1×	0.003	GCK
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.003	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	356.9×	0.003	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	356.9×	0.003	GCK
Glycolysis	1	285.5×	0.004	GCK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose catabolic process	1	2407.4×	0.002	GCK
regulation of potassium ion transport	1	1872.4×	0.002	GCK
NADP+ metabolic process	1	1532.0×	0.002	GCK
cellular response to leptin stimulus	1	1532.0×	0.002	GCK
glucose 6-phosphate metabolic process	1	1296.3×	0.002	GCK
regulation of glycolytic process	1	1203.7×	0.002	GCK
positive regulation of glycogen biosynthetic process	1	991.3×	0.002	GCK
negative regulation of gluconeogenesis	1	802.5×	0.002	GCK
calcium ion import	1	802.5×	0.002	GCK
canonical glycolysis	1	702.2×	0.003	GCK
intracellular glucose homeostasis	1	581.1×	0.003	GCK
regulation of insulin secretion	1	391.9×	0.004	GCK
glycolytic process	1	383.0×	0.004	GCK
glucose metabolic process	1	255.3×	0.004	GCK
response to glucose	1	255.3×	0.004	GCK
positive regulation of insulin secretion	1	255.3×	0.004	GCK
cellular response to insulin stimulus	1	170.2×	0.006	GCK
glucose homeostasis	1	130.6×	0.008	GCK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCK	5	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GCK	228

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GCK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.