SLC17A8

Chr 12AD

solute carrier family 17 member 8

Also known as: DFNA25, VGLUT3

NCBI Gene: 246213 ENSG00000179520 UniProt: Q8NDX2 OMIM: 607557

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]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.611 OMIM phenotype

Clinical Summary— SLC17A8

🧬

Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 220 VUS of 362 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SLC17A8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.001

Z-score 3.14

OE 0.36 (0.22–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.87 (0.79–0.96)

279 obs / 320.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.22–0.61)

0≤0.351.4

Missense OE?0.87 (0.79–0.96)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 27.9Missense obs/exp: 279 / 320.8Syn Z: 0.89

This gene — mechanism propensity

0.82top 10%

GOF

0.80top 10%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

362 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS220

Likely Benign85

Benign38

Conflicting11

Pathogenic

Likely Pathogenic

220

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	1	2	0	0	3
VUS	12	165	40	3	220
Likely Benign	0	3	50	32	85
Benign	0	1	33	4	38
Conflicting	—				11
Total	15	171	123	39	359

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap SLC17A8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →