GeneBe

SLC17A8

protein-coding

solute carrier family 17 member 8, the group of Solute carrier family 17

Gene summary

This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

Previous symbols:
  • DFNA25

MANE transcript

NM_139319.3

Inheritance

AD

ClinVar variants

P:5U:200B:56

Top phenotype

Deafness, autosomal dominant 25

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr12:100,357,074-100,422,055

External References & Databases

Ensembl (ENSG00000179520)NCBI Gene (246213)OMIM (607557)HGNC:20151GenCCUniProt (Q8NDX2)AlphaFoldClinVar (SLC17A8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~65.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The *SLC17A8* gene was first associated in relation to autosomal dominant nonsyndromic hearing loss in 2008 (Ruel et al., PMID: 18674745). At least 8 unique variants (missense, frameshift, splice site) have been reported in humans in 9 probands in 8​ publications (PMIDs: 18674745, 26797701, 28647561, 24082139, 26969326, 34440452, 33724713, 34145196). Variants in this gene segregated with disease in 28 additional members in two families (PMID: 18674745). This gene-disease relationship is supported by expression studies, two mouse models, a mouse rescue, and a zebrafish model (PMIDs: 18674745, 18215623, 18305245, 22841313, 24676347, 25122905). In summary, *SCL17A8* is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as Strong by the ClinGen Hearing Loss Working Group on 9/12/2018 as per SOP v6. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence (PMIDs: 24082139, 26969326, 34440452, 33724713).

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 25STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011568

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 25LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011568

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 25AD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11115382; 18674745Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC17A8 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 233
Inborn genetic diseasesTotal: 83
Autosomal dominant nonsyndromic hearing loss 25Total: 49
not specifiedTotal: 47
SLC17A8-related disorderTotal: 42
Auditory neuropathy spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139319.3. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
42
clinvar
3
clinvar
 47
missense
2
clinvar
185
clinvar
10
clinvar
 197
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
1
clinvar
7
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
 5
Total23200533261

Highest pathogenic variant AF is 0.0000030982428

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_139319.3RefSeqNP_647480.112MANE Select
ENST00000323346.10EnsemblENSP00000316909.412MANE Select
NM_001145288.2RefSeqNP_001138760.111Standard
ENST00000392989.3EnsemblENSP00000376715.311Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc17a8Danio rerio

Structure: neuromast hair cell

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Synaptic vesicle cycle - Homo sapiens (human)
  • Retrograde endocannabinoid signaling - Homo sapiens (human)
  • Glutamatergic synapse - Homo sapiens (human)
  • Nicotine addiction - Homo sapiens (human)
  • Synaptic Vesicle Pathway

Biological Process

  • neural retina development
  • ion transport
  • sodium ion transport
  • brain development
  • sensory perception of sound

Molecular Function

  • L-glutamate transmembrane transporter activity
  • neurotransmitter transporter activity
  • symporter activity

Cellular Component

  • multivesicular body
  • integral component of membrane
  • cell junction
  • integral component of synaptic vesicle membrane
  • synaptic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000323346
Coding exons
12
Length
64981
Individuals with no LoFs
125695
Homozygous LoFs
0
Heterozygous LoFs
53
Defined
125748
p
0.000211
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8302793210.8700.00001683868
Missense (PolyPhen)132160.720.821311892
Synonymous0.8861031150.8950.000006861124
Loss of Function3.141027.90.3580.00000129342

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000430.00043rare
Latino/Admixed American0.000140.00014rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish0.000320.00032rare
European (Non-Finnish)0.000210.00021rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Mediates the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. May also mediate the transport of inorganic phosphate. {ECO:0000269|PubMed:12151341}.;

Recessive Scores

pRec
0.142

Intolerance Scores

LoFtool
0.855
RVIS EVS
-0.96
RVIS percentile EVS
9.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.369

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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