SLC5A7

Chr 2ARAD

solute carrier family 5 member 7

Also known as: CHT, CHT1, CMS20, DHMNVP, HMN7A, HMND7, hCHT1

NCBI Gene: 60482 ENSG00000115665 UniProt: Q9GZV3

This gene encodes a sodium ion- and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. The protein transports choline from the extracellular space into presynaptic terminals for synthesis into acetylcholine. Increased choline uptake results from increased density of this protein in synaptosomal plasma membranes in response to depolarization of cholinergic terminals. Dysfunction of cholinergic signaling has been implicated in various disorders including depression, attention-deficit disorder, and schizophrenia. An allelic variant of this gene is associated with autosomal dominant distal hereditary motor neuronopathy type VIIA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

Primary Disease Associations & Inheritance

Myasthenic syndrome, congenital, 20, presynapticMIM #617143

Neuronopathy, distal hereditary motor, autosomal dominant 7MIM #158580

534

ClinVar variants

Pathogenic / LP

0.02

pLI score

Active trials

Clinical Summary— SLC5A7

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Gene-Disease Validity (ClinGen)

neuronopathy, distal hereditary motor, type 7A · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

34 Pathogenic / Likely Pathogenic· 294 VUS of 534 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.56LOEUF

pLI 0.015

Z-score 3.23

OE 0.31 (0.18–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

2.81Z-score

OE missense 0.56 (0.49–0.63)

180 obs / 321.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.31 (0.18–0.56)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.49–0.63)

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.1.02

0≤1.21.6

LoF obs/exp: 8 / 25.7Missense obs/exp: 180 / 321.6Syn Z: -0.14