Hyperinsulinemic hypoglycemia, familial, 1: genes and variants

Genes linked to Hyperinsulinemic hypoglycemia, familial, 1

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  31 disease-causing and 161 uncertain variants in ABCC8 are linked to Hyperinsulinemic hypoglycemia, familial, 1.

• KCNJ11: ATP-sensitive inward rectifier potassium channel 11

  Together with SUR1, its ATP-sensitive potassium conductance couples pancreatic beta-cell metabolism to membrane depolarization and insulin secretion. Activating variants cause neonatal diabetes, whereas loss-of-function variants can cause congenital hyperinsulinism.

  7 disease-causing and 35 uncertain variants in KCNJ11 are linked to Hyperinsulinemic hypoglycemia, familial, 1.

• GCK: Hexokinase-4

  It sets the glucose threshold for insulin secretion in pancreatic beta cells and controls hepatic glucose phosphorylation after meals. Heterozygous loss-of-function variants cause GCK-MODY, stronger loss can cause neonatal diabetes, and activating variants can cause hyperinsulinemic hypoglycemia.

  7 disease-causing and 10 uncertain variants in GCK are linked to Hyperinsulinemic hypoglycemia, familial, 1.

Where Hyperinsulinemic hypoglycemia, familial, 1 variants cluster

• ABCC8 ABC transporter 2 (positions 1344–1578): 15 of 31 disease-causing changes, 3.3× more than its size predicts.
• ABCC8 Cytoplasmic (positions 1175–1248): 4 of 31 disease-causing changes, 2.8× more than its size predicts.

Known disease-causing variants in Hyperinsulinemic hypoglycemia, familial, 1

Which prediction tools work for Hyperinsulinemic hypoglycemia, familial, 1

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CADD: 96 out of 100
• REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 83 out of 100
• SIFT: 83 out of 100
• MutPred2: 71 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 61 out of 100

Same protein, different disease

• Type 2 diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (27 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (22 disease-causing).
• Familial hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (20 disease-causing).
• Diabetes mellitus, transient neonatal, 2 is also caused by ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (19 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (17 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall partly in the same places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall partly in the same places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 disease-causing).
• Monogenic diabetes is also caused by GCK variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (235 disease-causing).
• Maturity-onset diabetes of the young is also caused by GCK variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (68 disease-causing).

Diseases related to Hyperinsulinemic hypoglycemia, familial, 1

• Monogenic diabetes, also linked to ABCC8, GCK and KCNJ11
• Maturity-onset diabetes of the young, also linked to ABCC8, GCK and KCNJ11
• Type 2 diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
• Familial hyperinsulinism, also linked to ABCC8, GCK and KCNJ11
• Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8 and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8 and KCNJ11
• Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
• Diabetes mellitus, also linked to ABCC8 and KCNJ11
• Atrial septal defect, also linked to ABCC8
• Pulmonary arterial hypertension, also linked to ABCC8
• Hereditary hyperinsulinism, also linked to ABCC8

Frequently asked questions

Which genes are linked to Hyperinsulinemic hypoglycemia, familial, 1?

In CATVariant, Hyperinsulinemic hypoglycemia, familial, 1 is linked to 3 analyzed proteins: ABCC8 (ATP-binding cassette sub-family C member 8), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11) and GCK (Hexokinase-4).

How many genetic variants are linked to Hyperinsulinemic hypoglycemia, familial, 1?

286 variants: 45 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 206 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hyperinsulinemic hypoglycemia, familial, 1 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hyperinsulinemic hypoglycemia, familial, 1?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 34 disease-causing and 19 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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