Familial hypokalemia-hypomagnesemia: genes and variants

Genes linked to Familial hypokalemia-hypomagnesemia

• SLC12A3: Solute carrier family 12 member 3

  It reabsorbs sodium and chloride in the distal convoluted tubule and is a major determinant of renal salt and magnesium handling. Biallelic loss-of-function variants cause Gitelman syndrome with hypokalemic metabolic alkalosis, hypomagnesemia, and low urinary calcium.

  115 disease-causing and 224 uncertain variants in SLC12A3 are linked to Familial hypokalemia-hypomagnesemia.

• IDUA: Alpha-L-iduronidase

  It removes terminal alpha-L-iduronic acid residues during lysosomal degradation of dermatan and heparan sulfate. Biallelic loss-of-function variants cause mucopolysaccharidosis type I, spanning severe Hurler syndrome to attenuated Scheie-spectrum disease.

  1 disease-causing and 0 uncertain variants in IDUA are linked to Familial hypokalemia-hypomagnesemia.

Weakly linked (only a few uncertain records): SLC12A1 and CASR.

Where Familial hypokalemia-hypomagnesemia variants cluster

• SLC12A3 Scissor helix (positions 615–630): 5 of 115 disease-causing changes, 2.8× more than its size predicts.
• SLC12A3 Extracellular (positions 394–453): 12 of 115 disease-causing changes, 1.8× more than its size predicts.
• SLC12A3 Transmembrane (positions 339–360): 6 of 115 disease-causing changes, 2.4× more than its size predicts.
• SLC12A3 Transmembrane (positions 168–189): 5 of 115 disease-causing changes, 2.0× more than its size predicts.
• SLC12A3 Transmembrane (positions 454–477): 5 of 115 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Familial hypokalemia-hypomagnesemia

Showing 60 of 116.

Which prediction tools work for Familial hypokalemia-hypomagnesemia

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

• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 92 out of 100
• SIFT: 89 out of 100
• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 86 out of 100
• MetaLR: 78 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Renal tubulopathies is also caused by SLC12A3 variants; they fall in the same places as the Familial hypokalemia-hypomagnesemia variants (14 disease-causing).
• Mucopolysaccharidosis is also caused by IDUA variants; they fall mostly in different places as the Familial hypokalemia-hypomagnesemia variants (80 disease-causing).
• Hurler syndrome is also caused by IDUA variants; they fall mostly in different places as the Familial hypokalemia-hypomagnesemia variants (16 disease-causing).
• Mucopolysaccharidosis, MPS-I-S is also caused by IDUA variants; they fall mostly in different places as the Familial hypokalemia-hypomagnesemia variants (6 disease-causing).
• Mucopolysaccharidosis, MPS-I-H/S is also caused by IDUA variants; they fall mostly in different places as the Familial hypokalemia-hypomagnesemia variants (3 disease-causing).

Diseases related to Familial hypokalemia-hypomagnesemia

• Mucopolysaccharidosis, also linked to IDUA
• Nephrotic syndrome, also linked to SLC12A3
• Renal tubulopathies, also linked to SLC12A3
• Hurler syndrome, also linked to IDUA
• Mucopolysaccharidosis, MPS-I-S, also linked to IDUA
• Myocardial infarction, also linked to SLC12A3
• Bartter syndrome, also linked to SLC12A3
• Mucopolysaccharidosis, MPS-I-H/S, also linked to IDUA
• Chronic kidney disease, also linked to SLC12A3
• Renal tubular acidosis, also linked to SLC12A3

Frequently asked questions

Which genes are linked to Familial hypokalemia-hypomagnesemia?

In CATVariant, Familial hypokalemia-hypomagnesemia is linked to 2 analyzed proteins: SLC12A3 (Solute carrier family 12 member 3) and IDUA (Alpha-L-iduronidase).

How many genetic variants are linked to Familial hypokalemia-hypomagnesemia?

351 variants: 116 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 227 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial hypokalemia-hypomagnesemia 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 Familial hypokalemia-hypomagnesemia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 100 disease-causing and 52 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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