SLC12A3

Chr 16AR

solute carrier family 12 member 3

Also known as: NCC, NCCT, TSC

NCBI Gene: 6559 ENSG00000070915 UniProt: P55017 OMIM: 600968

This gene encodes the thiazide-sensitive sodium-chloride cotransporter that mediates sodium and chloride reabsorption in the distal convoluted tubule of the kidney. Mutations cause Gitelman syndrome, an autosomal recessive disorder characterized by hypokalemic alkalosis, hypomagnesemia, low urinary calcium, and increased renin activity with normal blood pressure. The gene shows low constraint against loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Gitelman syndromeMIM #263800

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Gitelman syndrome; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.20

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — SLC12A3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.36

OE 0.95 (0.75–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.94Z-score

OE missense 1.11 (1.04–1.18)

682 obs / 616.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.95 (0.75–1.20)

0≤0.351.4

Missense OE?1.11 (1.04–1.18)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 50 / 52.8Missense obs/exp: 682 / 616.6Syn Z: -1.08

Background carrier burden — how many people carry a rare variant somewhere in SLC12A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 26

1,429 rare PASS variants

Rare truncating (LoF)

1 in 350

250 rare PASS variants

Rare synonymous (reference)

1 in 56

577 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC12A3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 35	1 in 330
South Asian	~43k	1 in 33	1 in 370
Remaining (unassigned)	~30k	1 in 24	1 in 320
European (Finnish)	~27k	1 in 89	1 in 5,300
Admixed American	~22k	1 in 28	1 in 680
African / African American	~21k	1 in 34	1 in 420
East Asian	~20k	1 in 32	1 in 460
Ashkenazi Jewish	~13k	1 in 130	1 in 2,600
Middle Eastern	~2,884	1 in 33	1 in 410

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 26 of 26 coding exons well covered in gnomAD exomes. Genomes: 24 of 26 (exons 9, 24 below).? see exons ↓