SLC6A17

protein-coding

solute carrier family 6 member 17, the group of Solute carrier family 6

Gene summary

The protein encoded by this gene is a member of the SLC6 family of transporters, which are responsible for the presynaptic uptake of most neurotransmitters. The encoded vesicular transporter is selective for proline, glycine, leucine and alanine. In mouse, the strongest expression of this gene was in cortical and hippocampal tissues where expression increased during embryonic brain development and peaked postnatally. Defects in this gene cause a form of autosomal recessive intellectual disability. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001010898.4

Inheritance

ClinVar variants

P:2U:99B:34

Top phenotype

Intellectual developmental disorder, autosomal recessive 48

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr1:110,150,494-110,202,202

External References & Databases

Ensembl (ENSG00000197106)

Transcript & Mutation Effects

hg38 • Region Span ~51.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: G2P

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 48LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: Illumina

intellectual developmental disorder, autosomal recessive 48MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 48SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 48MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: ClinGen

Th*e SLC6A17 g*ene was first reported in association with autosomal recessive intellectual disability type 48 in 2015 (Iqbal Z et al., PMID: 25704603). To date, at least five affected individuals from two unrelated families have been described in the literature (family 1 with two probands and family 2 with three probands). Across two publications, three missense variants have been reported; however, detailed functional characterization has been performed for only two variants, which were included in this curation (Iqbal Z et al., PMID: 25704603). Overall, functional data support a loss-of-function disease mechanism. This gene-disease relationship is also supported by animal models where studies demonstrate that loss of SLC6A17 impairs glutamine transport into presynaptic compartments. Furthermore, both Slc6a17 knockout mice and mice homozygous for the P633R patient variant show significantly reduced glutamine levels in synaptic vesicles (Jiao X et al., PMID: 37440432). Additionally, NTT4 (SLC6A17) knockout mice exhibit impaired retention of conditioned memory associations when conditioned and unconditioned stimuli are separated by a longer temporal gap which recapitulates the phenotypes described in the literature (Nicoli AL et al., PMID: 40436200). In summary, there is moderate evidence supporting a gene–disease relationship between SLC6A17 and intellectual disability type 48. This classification was approved by the ClinGen IEM GCEP at the meeting on February 13th, 2026 (SOP Version 12).

intellectual developmental disorder, autosomal recessive 48LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014559

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 48AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25704603

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC6A17 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 98

not providedTotal: 28

Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndromeTotal: 19

SLC6A17-related disorderTotal: 5

Long QT syndromeTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001010898.4. 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			1 clinvar	24 clinvar	1 clinvar	26
missense	2 clinvar		94 clinvar	8 clinvar	1 clinvar	105
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	0	99	32	2	135

Highest pathogenic variant AF is 0.0000041044163

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001010898.4	RefSeq	NP_001010898.1	11	MANE Select
ENST00000331565.5	Ensembl	ENSP00000330199.3	11	MANE Select
ENST00000873463.1	Ensembl	ENSP00000543522.1	11	Standard
ENST00000873463.2	Ensembl	ENSP00000543522.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nuclear Receptors Meta-Pathway
NRF2 pathway

Biological Process

brain development
neutral amino acid transport
glycine transport
leucine transport
proline transport

Molecular Function

neurotransmitter:sodium symporter activity

Cellular Component

integral component of plasma membrane
synaptic vesicle
cell junction
integral component of synaptic vesicle membrane
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331565
Coding exons: 11
Length: 51717
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.39	313	456	0.686	0.0000279	4752
Missense (PolyPhen)		116	192.89	0.60137		2004
Synonymous	1.05	181	200	0.905	0.0000133	1470
Loss of Function	3.86	6	28.0	0.214	0.00000132	321

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a sodium-dependent vesicular transporter selective for proline, glycine, leucine and alanine. In contrast to other members of this neurotransmitter transporter family, does not appear to be chloride-dependent (By similarity). {ECO:0000250|UniProtKB:P31662}.;
Disease: DISEASE: Mental retardation, autosomal recessive 48 (MRT48) [MIM:616269]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT48 patients show moderate to severe intellectual disability and additional features including progressive tremor, speech impairment, and sometimes behavioral problems. {ECO:0000269|PubMed:25704603}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.244
RVIS EVS: -0.57
RVIS percentile EVS: 18.9

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.236

Gene Damage Prediction

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