SLC6A5

Chr 11ADAR

solute carrier family 6 member 5

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

NCBI Gene: 9152 ENSG00000165970 UniProt: Q9Y345 OMIM: 604159

This gene encodes a sodium- and chloride-dependent glycine transporter that terminates glycinergic neurotransmission by reuptaking glycine into presynaptic terminals. Mutations cause hyperekplexia 3, a neurological disorder characterized by exaggerated startle responses and neonatal apnea. The condition follows both autosomal dominant and autosomal recessive inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.971 OMIM phenotype

Clinical Summary— SLC6A5

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Gene-Disease Validity (ClinGen)

hyperekplexia 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

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

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ClinVar Variants

73 unique Pathogenic / Likely Pathogenic· 351 VUS of 892 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC6A5

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?

0.97LOEUF

pLI 0.000

Z-score 1.72

OE 0.71 (0.52–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.09Z-score

OE missense 1.01 (0.94–1.10)

442 obs / 436.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.52–0.97)

0≤0.351.4

Missense OE?1.01 (0.94–1.10)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 28 / 39.7Missense obs/exp: 442 / 436.5Syn Z: -1.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC6A5-related hyperekplexiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.82top 10%

LOF

0.2970th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNIn vitro functional expression studies showed that S510R formed intracellular aggregates, abolished glycine uptake, and caused a dominant-negative effect.1

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

References

1.PMID 16751771 ↗

ClinVar Variant Classifications

892 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42

Likely Pathogenic31

VUS351

Likely Benign365

Benign78

Conflicting25

Pathogenic

Likely Pathogenic

351

VUS

365

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	6	6	0	42
Likely Pathogenic	21	9	1	0	31
VUS	5	323	21	2	351
Likely Benign	0	13	116	236	365
Benign	0	10	56	12	78
Conflicting	—				25
Total	56	361	200	250	892

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap SLC6A5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →