SLC6A5

Chr 11ADAR

solute carrier family 6 member 5

Also known as: GLYT-2, GLYT2, HKPX3, NET1

NCBI Gene: 9152ENSG00000165970UniProt: Q9Y345

This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Hyperekplexia 3MIM #614618
ADAR
400
ClinVar variants
51
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SLC6A5
🧬
Gene-Disease Validity (ClinGen)
hyperekplexia 3 · ARDefinitive

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
51 Pathogenic / Likely Pathogenic· 155 VUS of 400 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.97LOEUF
pLI 0.000
Z-score 1.72
OE 0.71 (0.52–0.97)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.09Z-score
OE missense 1.01 (0.94–1.10)
442 obs / 436.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.71 (0.52–0.97)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.94–1.10)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.19
0≤1.21.6
LoF obs/exp: 28 / 39.7Missense obs/exp: 442 / 436.5Syn Z: -1.99

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic19
VUS155
Likely Benign158
Benign28
Conflicting8
32
Pathogenic
19
Likely Pathogenic
155
VUS
158
Likely Benign
28
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
1
22
0
32
Likely Pathogenic
11
6
2
0
19
VUS
2
139
13
1
155
Likely Benign
0
9
51
98
158
Benign
0
10
8
10
28
Conflicting
—8
Total2216596109400

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC6A5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC6A5-related hyperekplexia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperekplexia 3

MIM #614618

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — SLC6A5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Myoclonus.
Espay AJ et al.·Continuum (Minneap Minn)
2013Review
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Hyperekplexia: A Single-Center Experience.
Dolu MH et al.·J Child Neurol
2024
Hereditary Hyperekplexia in Saudi Arabia.
Aldhilan A et al.·Pediatr Neurol
2022
Neonatal Hyperekplexia: Is It Still a Diagnostic Challenge? Evidence From a Systematic Review.
Falsaperla R et al.·J Child Neurol
2024Review
STARDEV Study: Neurodevelopmental Trajectory and Long-Term Outcomes of Patients with Startle Disease/Hyperekplexia.
Pina D et al.·Mov Disord Clin Pract
2025Cohort
GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations.
Hauf K et al.·Neurochem Int
2020
Hyperekplexia: treatment of a severe phenotype and review of the literature.
Mineyko A et al.·Can J Neurol Sci
2011Review
A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes.
Bogdanik LP et al.·PLoS One
2012Functional
Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.
Carta E et al.·J Biol Chem
2012Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Hyperekplexia

Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory

RECRUITING
NCT05652101Hospices Civils de LyonStarted 2023-04-24
collection of medical dataVineland Adaptive Behaviour Scales (VABS2) questionnaire

External Resources

Links to major genomics databases and tools