GeneBe

SLC26A4

protein-coding

solute carrier family 26 member 4, the group of Solute carrier family 26

Gene summary

Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

Previous symbols:
  • DFNB4

MANE transcript

NM_000441.2

Inheritance

AR, AD

ClinVar variants

P:664U:329B:380

Top phenotype

Pendred syndrome; Deafness, autosomal recessive 4, with enlarged vestibular aqueduct

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr7:107,660,828-107,717,809

External References & Databases

Ensembl (ENSG00000091137)NCBI Gene (5172)OMIM (605646)HGNC:8818GenCCUniProt (O43511)AlphaFoldClinVar (SLC26A4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~57.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Pendred syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Natera

thyroid hypoplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019861

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010933

Submitter: Ambry Genetics

Pendred syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010933

Submitter: PanelApp Australia

Pendred syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: ClinGen

The association between SLC26A4 and autosomal recessive Pendred syndrome is well-established and over 500 variants have been reported, including missense, nonsense, frameshift, splice, in-frame indel, and large deletion variants. The hearing loss associated with SLC26A4 is typically congenital, pre-, or peri-lingual in onset and caused by enlarged vestibular aqueduct (EVA). An incomplete partitioning defect of the cochlea may also be present. Goiter and/or hypothyroidism are an incompletely penetrant feature of Pendred syndrome and may not present until the second decade of life (Pryor 2005, Soh 2015). There may be variable expression of the thyroid features, even within families with the same pathogenic variants. Additionally, a large percentage of individuals with hearing loss and EVA lack variants on one or both alleles of SLC26A4. Individuals with a single mutation appear to be less likely to develop the thyroid features, but may have similar recurrence risks as individuals found to harbor two biallelic pathogenic variants (Pryor 2005, Chattaraj 2014). This gene-disease association is supported by animal models, evidence of expression in the ear and thyroid, and in vitro biochemical studies. In summary, SLC26A4 is definitively associated with autosomal recessive Pendred syndrome. 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 Hearing Loss Working Group on 6/7/2017.

Pendred syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Orphanet

athyreosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019855

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010933

Submitter: Labcorp Genetics (formerly Invitae)

Pendred syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Pendred syndrome; Deafness, autosomal recessive 4, with enlarged vestibular aqueductAR

Manifestation: Audiologic/Otolaryngologic; Endocrine

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In Pendred syndrome, surveillance for and treatment of thyroid abnormalities can be beneficial

Comments: Promoter variants have been reported as causative; Digenic inheritance (with KCNJ10) has been reported

Refs: 9398842; 9500541; 9920104; 10190331; 10902795; 11317356; 14508505; 15689455; 16570074; 17690912; 17503324; 19426954; 21488278; 20301640Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC26A4 variants in ClinVar

22 Conditions Cataloged
not providedTotal: 1189
Pendred syndromeTotal: 606
Autosomal recessive nonsyndromic hearing loss 4Total: 533
not specifiedTotal: 190
Rare genetic deafnessTotal: 66
Inborn genetic diseasesTotal: 53
SLC26A4-related disorderTotal: 49
Hearing loss, autosomal recessiveTotal: 19

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000441.2. 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
5
clinvar
14
clinvar
348
clinvar
1
clinvar
 368
missense
58
clinvar
229
clinvar
310
clinvar
26
clinvar
5
clinvar
 628
nonsense
51
clinvar
39
clinvar
1
clinvar
 91
start loss
2
clinvar
3
clinvar
 5
frameshift
89
clinvar
84
clinvar
2
clinvar
 175
splice donor/acceptor (+/-2bp)
33
clinvar
71
clinvar
2
clinvar
 106
Total23343132937461373

Highest pathogenic variant AF is 0.001305661

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000441.2RefSeqNP_000432.120MANE Select
ENST00000644269.2EnsemblENSP00000494017.120MANE Select
ENST00000440056.1EnsemblENSP00000394760.13Standard
ENST00000644846.1EnsemblENSP00000494344.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Thyroid hormone synthesis - Homo sapiens (human)
  • Tyrosine metabolism
  • Biopterin metabolism
  • Transport of inorganic cations/anions and amino acids/oligopeptides
  • SLC-mediated transmembrane transport

Biological Process

  • ion transport
  • regulation of pH
  • sensory perception of sound
  • sulfate transport
  • inorganic anion transport

Molecular Function

  • secondary active sulfate transmembrane transporter activity
  • bicarbonate transmembrane transporter activity
  • chloride transmembrane transporter activity
  • iodide transmembrane transporter activity
  • sulfate transmembrane transporter activity

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000265715
Coding exons
20
Length
57175
Individuals with no LoFs
125497
Homozygous LoFs
0
Heterozygous LoFs
251
Defined
125748
p
0.000999
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-2.015284131.280.00002155029
Missense (PolyPhen)200170.331.17422165
Synonymous-0.2361641601.020.000009071577
Loss of Function0.6623539.50.8860.00000188496

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000880.00086rare
Latino/Admixed American0.000950.00093rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.00570.0057notable
Finnish00.0absent
European (Non-Finnish)0.000740.00073rare
South Asian0.000420.00042rare
Other0.000650.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Sodium-independent transporter of chloride and iodide. {ECO:0000269|PubMed:10192399}.;
Disease
DISEASE: Deafness, autosomal recessive, 4 (DFNB4) [MIM:600791]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB4 is associated with an enlarged vestibular aqueduct. {ECO:0000269|PubMed:10190331, ECO:0000269|PubMed:10700480, ECO:0000269|PubMed:11748854, ECO:0000269|PubMed:12676893, ECO:0000269|PubMed:14508505, ECO:0000269|PubMed:14679580, ECO:0000269|PubMed:19204907, ECO:0000269|PubMed:20108392, ECO:0000269|PubMed:20597900, ECO:0000269|PubMed:24051746, ECO:0000269|PubMed:28281779, ECO:0000269|PubMed:9500541}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.439

Intolerance Scores

LoFtool
0.0893
RVIS EVS
1.14
RVIS percentile EVS
92.34

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.192

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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