GeneBe

SLC12A3

protein-coding

solute carrier family 12 member 3, the group of Solute carrier family 12|MicroRNA protein coding host genes

Gene summary

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]

MANE transcript

NM_001126108.2

Inheritance

AR

ClinVar variants

P:513U:415B:533

Top phenotype

Gitelman syndrome

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr16:56,865,207-56,915,850

External References & Databases

Ensembl (ENSG00000070915)OMIM (600968)HGNC:10912GenCCUniProt (P55017)AlphaFoldClinVar (SLC12A3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~50.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Gitelman syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009904

Submitter: Labcorp Genetics (formerly Invitae)

Gitelman syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009904

Submitter: Natera

Gitelman syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009904

Submitter: Orphanet

Gitelman syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009904

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Gitelman syndromeAR

Manifestation: Cardiovascular; Renal

Intervention: Cardiovascular; Renal

Rationale: Surveillance for, treatment of, and prevention of electrolyte abnormalities may be beneficial; Individuals with cardiovascular manifestations (eg, arrhythmias such as QTc prolongation) that may warrant interventions have also been described

Comments: Individuals have been reported with cardiovascular manifestations

Refs: 5929460; 1436349; 81436349; 16120871; 17000984; 17981812; 22009145Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC12A3 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 1406
Familial hypokalemia-hypomagnesemiaTotal: 784
SLC12A3-related disorderTotal: 170
not specifiedTotal: 155
Inborn genetic diseasesTotal: 148
Renal tubulopathiesTotal: 41
Bartter syndromeTotal: 16
HypokalemiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001126108.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
26
clinvar
500
clinvar
 527
missense
32
clinvar
184
clinvar
384
clinvar
32
clinvar
1
clinvar
 633
nonsense
38
clinvar
27
clinvar
1
clinvar
 66
start loss
3
clinvar
 3
frameshift
72
clinvar
69
clinvar
2
clinvar
 143
splice donor/acceptor (+/-2bp)
33
clinvar
54
clinvar
2
clinvar
 89
Total17833541553211461

Highest pathogenic variant AF is 0.0015203538

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001126108.2RefSeqNP_001119580.226MANE Select
ENST00000563236.6EnsemblENSP00000456149.226MANE Select
NM_000339.3RefSeqNP_000330.326Standard
NM_001126107.2RefSeqNP_001119579.226Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc12a3Danio rerio

Structure: pronephric duct

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Diuretics Pathway, Pharmacodynamics
  • Polythiazide Action Pathway
  • Methyclothiazide Action Pathway
  • Bumetanide Action Pathway
  • Spironolactone Action Pathway

Biological Process

  • ion transport
  • sodium ion transport
  • cell volume homeostasis
  • sodium ion transmembrane transport
  • chloride ion homeostasis

Molecular Function

  • transporter activity
  • protein binding
  • sodium:potassium:chloride symporter activity
  • sodium ion transmembrane transporter activity
  • sodium:chloride symporter activity

Cellular Component

  • cytosol
  • plasma membrane
  • integral component of plasma membrane
  • membrane
  • apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000438926
Coding exons
26
Length
50644
Individuals with no LoFs
125522
Homozygous LoFs
0
Heterozygous LoFs
226
Defined
125748
p
0.000899
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.9366826171.110.00003926705
Missense (PolyPhen)242232.051.04292524
Synonymous-1.082762541.090.00001752052
Loss of Function0.3625052.80.9460.00000269578

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000930.00092rare
Latino/Admixed American0.000460.00046rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.00140.0012notable
Finnish00.0absent
European (Non-Finnish)0.00120.0012notable
South Asian0.00100.00098notable
Other0.000650.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the proinflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (By similarity). {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:21613606, ECO:0000269|PubMed:22009145}.;
Disease
DISEASE: Gitelman syndrome (GTLMNS) [MIM:263800]: An autosomal recessive disorder characterized by hypokalemic alkalosis in combination with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. Patients are often asymptomatic or present transient periods of muscular weakness and tetany, usually accompanied by abdominal pain, vomiting and fever. The phenotype is highly heterogeneous in terms of age at onset and severity. Cardinal features such as hypocalciuria and hypomagnesemia might also change during the life cycle of a given patient. It has overlapping features with Bartter syndrome. {ECO:0000269|PubMed:10616841, ECO:0000269|PubMed:10988270, ECO:0000269|PubMed:11168953, ECO:0000269|PubMed:11940055, ECO:0000269|PubMed:12008755, ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:15687331, ECO:0000269|PubMed:16429844, ECO:0000269|PubMed:17654016, ECO:0000269|PubMed:17873326, ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:26099046, ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:8900229, ECO:0000269|PubMed:8954067, ECO:0000269|PubMed:9734597}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.278

Intolerance Scores

LoFtool
0.0228
RVIS EVS
-1.62
RVIS percentile EVS
2.89

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.911

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.