GeneBe

SLC34A3

protein-coding

solute carrier family 34 member 3, the group of Solute carrier family 34

Gene summary

This gene encodes a member of SLC34A transporter family of proteins, and is expressed primarily in the kidney. It is involved in transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney. Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. Alternatively spliced transcript variants varying in the 5' UTR have been found for this gene.[provided by RefSeq, Apr 2010]

MANE transcript

NM_001177316.2

Inheritance

AR, SD

ClinVar variants

P:105U:361B:216

Top phenotype

Hypophosphatemic rickets with hypercalciuria, hereditary

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr9:137,230,757-137,236,555

External References & Databases

Ensembl (ENSG00000198569)NCBI Gene (142680)OMIM (609826)HGNC:20305GenCCUniProt (Q8N130)AlphaFoldClinVar (SLC34A3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.8 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary hypophosphatemic rickets with hypercalciuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009431

Submitter: Labcorp Genetics (formerly Invitae)

hereditary hypophosphatemic rickets with hypercalciuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009431

Submitter: Orphanet

hereditary hypophosphatemic rickets with hypercalciuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009431

Submitter: Natera

hereditary hypophosphatemic rickets with hypercalciuriaDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0009431

Submitter: Ambry Genetics

hereditary hypophosphatemic rickets with hypercalciuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009431

Submitter: ClinGen

*SLC34A3* was first reported in relation to autosomal recessive hereditary hypophosphatemic rickets with hypercalciuria in 2006 (Bergwitz et al., PMID: 16358214; and Ichikawa et al., PMID: 16849419). This condition is characterized by hypophosphatemic rickets; hypercalciuria; kidney stones; bone anomalies (such as short stature, osteopenia and bone pain); abnormal circulating vitamin D concentration; and kidney stones. Thirteen variants (missense, nonsense, frameshift, and splicing) that have been reported in at least eight probands in three publications are included in this curation (PMIDs: 16358214, 16849419, 31440709). An *SLC34A3* biallelic mutant genotype has also segregated with disease in nine affected individuals from one family (PMID: 16358214). The maximum score for genetic evidence (12 points) has been reached. The mechanism of disease appears to be loss-of-function (PMIDs: 16358214, 16849419, 31440709). This gene-disease relationship is also supported by experimental evidence (expression, biochemical function, functional alteration, mouse model; PMIDs: 11880379, 19570882, 22159077). Expression-level evidence shows that the gene is expressed in the kidney. Biochemical functional evidence shows that reduced phosphate uptake has been seen in affected patient plasma. Experimental evidence in xenopus oocytes with the same mutations found in affected humans shows reduced/lack of expression of the protein. Mutant mice have reduced body weight and bone anomalies, corresponding to short stature and bone anomalies seen in humans. In summary, there is definitive evidence supporting the relationship between *SLC34A3* and autosomal recessive hereditary hypophosphatemic rickets with hypercalciuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 11/17/2022 (SOP Version 9).

hereditary hypophosphatemic rickets with hypercalciuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009431

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypophosphatemic rickets with hypercalciuria, hereditaryAR

Manifestation: Renal

Intervention: Renal

Rationale: The condition can result in sequelae such as severe rickets, and supplementation (eg, with phosphate) can be effective to treat many sequelae

Comments: Heterozygotes may show mild manifestations

Refs: 2983203; 3796683; 1436310; 16358214; 16358215Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC34A3 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 626
Autosomal recessive hypophosphatemic bone diseaseTotal: 327
Inborn genetic diseasesTotal: 147
SLC34A3-related disorderTotal: 138
not specifiedTotal: 119
Kidney disorderTotal: 3
HypercalciuriaTotal: 2
Hypophosphatemic nephrolithiasis/osteoporosis 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001177316.2. 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
1
clinvar
11
clinvar
180
clinvar
2
clinvar
 195
missense
3
clinvar
18
clinvar
339
clinvar
31
clinvar
2
clinvar
 393
nonsense
7
clinvar
13
clinvar
2
clinvar
 22
start loss
2
clinvar
 2
frameshift
17
clinvar
11
clinvar
3
clinvar
 31
splice donor/acceptor (+/-2bp)
4
clinvar
28
clinvar
6
clinvar
1
clinvar
 39
Total32733612124682

Highest pathogenic variant AF is 0.0007227801

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001177316.2RefSeqNP_001170787.212MANE Select
ENST00000673835.1EnsemblENSP00000501114.112MANE Select
NM_001177317.2RefSeqNP_001170788.212Standard
NM_080877.3RefSeqNP_543153.212Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Transport of inorganic cations/anions and amino acids/oligopeptides
  • SLC-mediated transmembrane transport
  • Transport of small molecules
  • Type II Na+/Pi cotransporters
  • Sodium-coupled phosphate cotransporters

Biological Process

  • sodium ion transport
  • phosphate ion transport
  • cellular phosphate ion homeostasis
  • sodium ion transmembrane transport
  • sodium-dependent phosphate transport

Molecular Function

  • sodium:phosphate symporter activity
  • sodium-dependent phosphate transmembrane transporter activity

Cellular Component

  • plasma membrane
  • brush border
  • integral component of membrane
  • apical plasma membrane
  • brush border membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000538474
Coding exons
12
Length
5798
Individuals with no LoFs
125486
Homozygous LoFs
1
Heterozygous LoFs
212
Defined
125699
p
0.000848
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.294663941.180.00002713758
Missense (PolyPhen)188166.581.12861678
Synonymous-3.272511931.300.00001481367
Loss of Function0.2152122.10.9510.00000105222

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000400.00037rare
Latino/Admixed American0.000830.00081rare
Ashkenazi Jewish00.0absent
East Asian0.000330.00033rare
Finnish0.00120.0011notable
European (Non-Finnish)0.00120.0011notable
South Asian0.000620.00059rare
Other0.000830.00082rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane. Probably mediates 20-30% of the apical influx.;
Disease
DISEASE: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [MIM:241530]: Autosomal recessive form of hypophosphatemia characterized by reduced renal phosphate reabsorption and rickets. Increased serum levels of 1,25-dihydroxyvitamin D lead to increase in urinary calcium excretion. {ECO:0000269|PubMed:16358214, ECO:0000269|PubMed:16358215}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.173

Intolerance Scores

LoFtool
0.239
RVIS EVS
0.41
RVIS percentile EVS
76.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.770

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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