SLC5A7

protein-coding

solute carrier family 5 member 7, the group of Solute carrier family 5

Gene summary

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]

MANE transcript

NM_021815.5

Inheritance

AD, AR

ClinVar variants

P:24U:303B:151

Top phenotype

Myasthenic syndrome, congenital, 20, presynaptic

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr2:107,986,523-108,013,994

External References & Databases

Ensembl (ENSG00000115665)

Transcript & Mutation Effects

hg38 • Region Span ~27.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

distal hereditary motor neuropathy type 7SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015355

Submitter: Orphanet

congenital myasthenic syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014939

Submitter: G2P

neuronopathy, distal hereditary motor, type 7AMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008024

Submitter: Ambry Genetics

congenital myasthenic syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014939

Submitter: Genomics England PanelApp

neuronopathy, distal hereditary motor, type 7AMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008024

Submitter: ClinGen

SLC5A7: autosomal dominant CMT with vocal cord paresis, 09/28/2021 SLC5A7 encodes a presynaptic solute-carrier protein responsible for choline uptake from the synaptic cleft. In 2012, WES revealed a truncating variant in the last exon of SLC5A7 co-segregating in a large family (LOD score: 6.32) with distal motor neuropathy and vocal cord paresis (PMID: 23141292). The authors showed that choline uptake is significantly impaired, demonstrating a dominant negative effect on the wildtype allele. The same variant was recurrently reported again (PMID: 26786006), and so were three more truncating mutations all affecting the last exon of the gene in different populations. All of these changes were predicted to not undergo nonsense-mediated RNA decay (PMIDs: 29582019, 29782645). In addition, the described phenotype was very consistent as well, sparing the sensory system, but commonly involving vocal cord paresis. In parallel, SLC5A7 was first described in the context of autosomal recessive congenital myasthenic syndrome in 2016 (MIM: 617143). Based on the autosomal dominant mode of inheritance with the dominant negative effect, the panel agreed on splitting the neuropathy from the myasthenia phenotype for the present curation. Experimental evidence showed that SLC5A7 is expressed in the neuromuscular junction (PMID: 15173594) and that loss of function results in an impaired choline uptake (PMID: 23132865). An animal model demonstrated that heterozygous KO mice are more vulnerable to choline uptake inhibitors than wildtype animals (PMID: 15173594). In summary, truncating mutations in the last exon of SLC5A7 are linked to a specific molecular mechanism and associated with a distinct phenotype. More reports will solidify the gene-disease relationship in the future. Based on the curated evidence, we classify the gene-disease relationship of SLC5A7 and autosomal dominant motor neuropathy with vocal cord paresis as moderate. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.

congenital myasthenic syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014939

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, type 7ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008024

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, type 7ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008024

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, type 7ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008024

Submitter: PanelApp Australia

congenital myasthenic syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014939

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital, 20, presynapticAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: The condition involves muscular weakness, and medical managament (with AChE inhibitors) has been described as beneficial in some individuals

Refs: 11294660; 23141292; 27569547

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC5A7 variants in ClinVar

10 Conditions Cataloged

Congenital myasthenic syndrome 20Total: 488

Neuronopathy, distal hereditary motor, type 7ATotal: 487

not providedTotal: 94

Inborn genetic diseasesTotal: 89

SLC5A7-related disorderTotal: 33

not specifiedTotal: 25

Charcot-Marie-Tooth disease type 2Total: 1

Distal spinal muscular atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021815.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	138 clinvar		142
missense	1 clinvar	8 clinvar	286 clinvar	11 clinvar	2 clinvar	308
nonsense	1 clinvar	1 clinvar	6 clinvar			8
start loss						0
frameshift	4 clinvar	3 clinvar	5 clinvar			12
splice donor/acceptor (+/-2bp)		6 clinvar	2 clinvar			8
Total	6	18	303	149	2	478

Highest pathogenic variant AF is 0.000011151726

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021815.5	RefSeq	NP_068587.1	8	MANE Select
ENST00000264047.3	Ensembl	ENSP00000264047.2	8	MANE Select
NM_001305005.3	RefSeq	NP_001291934.1	8	Standard
NM_001305006.3	RefSeq	NP_001291935.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Choline metabolism in cancer - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)
Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction)
Nuclear Receptors Meta-Pathway
NRF2 pathway

Biological Process

sodium ion transport
neurotransmitter secretion
synaptic transmission, cholinergic
neuromuscular synaptic transmission
acetylcholine biosynthetic process

Molecular Function

choline:sodium symporter activity
choline transmembrane transporter activity
choline binding

Cellular Component

plasma membrane
integral component of membrane
cell junction
axon
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264047
Coding exons: 8
Length: 27472
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.81	180	322	0.560	0.0000164	3729
Missense (PolyPhen)		32	100.52	0.31834		1163
Synonymous	-0.138	125	123	1.02	0.00000663	1213
Loss of Function	3.23	8	25.7	0.311	0.00000136	294

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transmembrane transporter that imports choline from the extracellular space into the neuron with high affinity. Choline uptake is the rate-limiting step in acetylcholine synthesis. Sodium ion- and chloride ion-dependent. {ECO:0000269|PubMed:11027560, ECO:0000269|PubMed:27569547}.;
Disease: DISEASE: Neuronopathy, distal hereditary motor, 7A (HMN7A) [MIM:158580]: A neuromuscular disorder. Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMN7A is characterized by onset in the second decade of progressive distal muscle wasting and weakness affecting the upper and lower limbs and resulting in walking difficulties and hand grip. There is significant muscle atrophy of the hands and lower limbs. The disorder is associated with vocal cord paresis due to involvement of the tenth cranial nerve. {ECO:0000269|PubMed:23141292}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 20, presynaptic (CMS20) [MIM:617143]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS20 is an autosomal recessive, pre-synaptic form characterized by severe hypotonia and episodic apnea soon after birth, generalized limb fatigability and weakness, delayed walking, ptosis, poor sucking and swallowing. {ECO:0000269|PubMed:27569547}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.214

Intolerance Scores

RVIS EVS: 0.24
RVIS percentile EVS: 69.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.836

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium