SLC26A5

protein-coding

solute carrier family 26 member 5, the group of Solute carrier family 26

Gene summary

This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

Previous symbols:

PRES

MANE transcript

NM_198999.3

Inheritance

ClinVar variants

P:24U:144B:60

Top phenotype

Deafness, autosomal recessive 61

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr7:103,352,730-103,446,207

External References & Databases

Ensembl (ENSG00000170615)

Transcript & Mutation Effects

hg38 • Region Span ~93.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

SLC26A5 was first reported in relation to autosomal recessive nonsyndromic hearing loss (ARNSHL) in 2003 (Liu et al.; PMID: 12719379). Six variants (missense, nonsense, 5' UTR splicing) have been reported in four probands in four publications, however the association was only scored in one proband as other variants did not have sufficient evidence for pathogenicity (PMIDs: 24164807, 12719379, 17786286, 26969326). This gene-disease relationship has been studied in at least one case-control study at the aggregate variant level (PMID: 19492055). No statistically significant difference was found between patients and controls in the frequency of the identified variants. The mechanism for disease is reported to be loss of function (PMIDs: 24164807, 18466744, 12239568). This gene-disease association is also supported by mouse models, biochemical function studies, and expression studies (PMIDs: 12239568, 10821263, 11423665, 12719379, 18466744, 27091614, 17998209). There is strong evidence that loss of SLC26A5 causes hearing loss in mice, yet there is limited evidence in humans. Researchers have posited that humans have a compensatory mechanism that mice do not have (Hosoya et al. 2016; PMID: 27091614). Due to the lack of convincing human patients, the Hearing Loss Gene Curation Expert Panel classified this gene-disease relationship as Limited. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss Gene Curation Expert Panel on 12/19/2017. It was reevaluated on 1/19/2022 (SOP v8). As a result of this reevaluation, the classification did not change.

autosomal recessive nonsyndromic hearing loss 61MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013471

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013471

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 61MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013471

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 61AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Heterozygosity has been observed in individuals with hearing loss as well, indicating possible semidominance

Refs: 12719379; 24164807

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC26A5 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 205

Inborn genetic diseasesTotal: 85

not specifiedTotal: 27

SLC26A5-related disorderTotal: 23

Autosomal recessive nonsyndromic hearing loss 61Total: 18

Nonsyndromic genetic hearing lossTotal: 1

Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198999.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	45 clinvar	1 clinvar	47
missense	1 clinvar	2 clinvar	138 clinvar	12 clinvar	1 clinvar	154
nonsense	5 clinvar		1 clinvar			6
start loss						0
frameshift	8 clinvar	2 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)		6 clinvar	3 clinvar	1 clinvar		10
Total	14	10	144	58	2	228

Highest pathogenic variant AF is 0.00003594015

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198999.3	RefSeq	NP_945350.1	18	MANE Select
ENST00000306312.8	Ensembl	ENSP00000304783.3	18	MANE Select
NM_001167962.2	RefSeq	NP_001161434.1	17	Standard
NM_001321787.2	RefSeq	NP_001308716.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

response to ischemia
sensory perception of sound
regulation of cell shape
response to salicylic acid
response to auditory stimulus

Molecular Function

transcription factor binding
secondary active sulfate transmembrane transporter activity
bicarbonate transmembrane transporter activity
chloride transmembrane transporter activity
sulfate transmembrane transporter activity

Cellular Component

cytoplasm
integral component of plasma membrane
basolateral plasma membrane
lateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306312
Coding exons: 18
Length: 93448
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.901	355	406	0.874	0.0000210	4821
Missense (PolyPhen)		188	229.35	0.81971		2750
Synonymous	1.14	138	156	0.884	0.00000901	1508
Loss of Function	2.88	18	36.9	0.488	0.00000191	465

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Motor protein that converts auditory stimuli to length changes in outer hair cells and mediates sound amplification in the mammalian hearing organ. Prestin is a bidirectional voltage- to-force converter, it can operate at microsecond rates. It uses cytoplasmic anions as extrinsic voltage sensors, probably chloride and bicarbonate. After binding to a site with millimolar affinity, these anions are translocated across the membrane in response to changes in the transmembrane voltage. They move towards the extracellular surface following hyperpolarization, and towards the cytoplasmic side in response to depolarization. As a consequence, this translocation triggers conformational changes in the protein that ultimately alter its surface area in the plane of the plasma membrane. The area decreases when the anion is near the cytoplasmic face of the membrane (short state), and increases when the ion has crossed the membrane to the outer surface (long state). So, it acts as an incomplete transporter. It swings anions across the membrane, but does not allow these anions to dissociate and escape to the extracellular space. Salicylate, an inhibitor of outer hair cell motility, acts as competitive antagonist at the prestin anion-binding site (By similarity). {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 61 (DFNB61) [MIM:613865]: 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. {ECO:0000269|PubMed:12719379}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.310

Intolerance Scores

LoFtool: 0.0406
RVIS EVS: -0.35
RVIS percentile EVS: 29.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.156

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium