SLC12A1

Chr 15AR

solute carrier family 12 member 1

Also known as: BSC, BSC-1, BSC1, CCC2, NKCC2

NCBI Gene: 6557 ENSG00000074803 UniProt: Q13621 OMIM: 600839

This gene encodes a sodium-potassium-chloride cotransporter expressed on the luminal membrane of the thick ascending limb of Henle's loop, where it mediates NaCl reabsorption and plays an essential role in urine concentration and volume regulation. Mutations cause Bartter syndrome type 1, an autosomal recessive tubulopathy affecting kidney function. The gene shows extremely low tolerance to loss-of-function variants (pLI near 1), indicating that complete loss of function is highly deleterious.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.821 OMIM phenotype

Clinical Summary— SLC12A1

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Gene-Disease Validity (ClinGen)

obsolete antenatal Bartter syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

137 unique Pathogenic / Likely Pathogenic· 383 VUS of 1103 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC12A1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.63

OE 0.62 (0.47–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.16Z-score

OE missense 0.86 (0.80–0.93)

502 obs / 580.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.47–0.82)

0≤0.351.4

Missense OE?0.86 (0.80–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 35 / 56.3Missense obs/exp: 502 / 580.7Syn Z: -0.60

This gene — mechanism propensity

0.77top 25%

GOF

0.79top 10%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1103 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic79

VUS383

Likely Benign459

Benign69

Conflicting47

Pathogenic

Likely Pathogenic

383

VUS

459

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	1	4	0	58
Likely Pathogenic	58	18	3	0	79
VUS	8	333	36	6	383
Likely Benign	0	8	223	228	459
Benign	0	1	64	4	69
Conflicting	—				47
Total	119	361	330	238	1,095

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap SLC12A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →