GeneBe

SLC1A4

protein-coding

solute carrier family 1 member 4, the group of Solute carrier family 1

Gene summary

The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability. [provided by RefSeq, Jan 2017]

MANE transcript

NM_003038.5

Inheritance

AR, AD

ClinVar variants

P:38U:127B:212

Top phenotype

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr2:64,988,477-65,023,865

External References & Databases

Ensembl (ENSG00000115902)NCBI Gene (6509)OMIM (600229)HGNC:10942GenCCUniProt (P43007)AlphaFoldClinVar (SLC1A4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~35.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014725

Submitter: PanelApp Australia

spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014725

Submitter: G2P

spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014725

Submitter: Labcorp Genetics (formerly Invitae)

spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014725

Submitter: ClinGen

SLC1A4 was first reported in relation to autosomal recessive spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome in 2015 (Srour M, et al., 2015, PMID: 25930971). At least 9 unique variants (missense, nonsense and small deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs: 25930971, 27711071, 29989513, 29652076, 26041762, 27193218, 30125339). Variants in this gene segregated with disease in 3 additional family members. More evidence of additional individuals with these 9 variants are available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the biochemical function of ASCT1, an L-serine transporter (PMID: 15099708) expressed in the brain (PMID: 12533615), as well as its functional alteration and phenotypic recapitulation in a knockout mouse model (PMID: 30185558). L-serine is a non-essential amino acid in extra-neural tissues; however, its de novo synthesis within the brain is essential because of the limited permeability of the blood–brain barrier for L-serine. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1 (encoded by SLC1A4). SLC1A4 disruption impairs brain development and function by decreasing its export from astrocytes. In summary, SLC1A4 is definitively associated with autosomal recessive spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014725

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic tetraplegia, thin corpus callosum, and progressive microcephalyAR

Manifestation: 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: 25930971; 26041762; 26138499; 29989513; 31763347Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC1A4 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 363
Inborn genetic diseasesTotal: 48
not specifiedTotal: 34
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeTotal: 32
SLC1A4-related disorderTotal: 11
SLC1A4-related spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndromeTotal: 1
MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003038.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
198
clinvar
3
clinvar
 202
missense
3
clinvar
6
clinvar
120
clinvar
9
clinvar
2
clinvar
 140
nonsense
3
clinvar
2
clinvar
1
clinvar
 6
start loss
1
clinvar
 1
frameshift
10
clinvar
6
clinvar
1
clinvar
 17
splice donor/acceptor (+/-2bp)
3
clinvar
4
clinvar
4
clinvar
 11
Total20181272075377

Highest pathogenic variant AF is 0.0001226857

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003038.5RefSeqNP_003029.28MANE Select
ENST00000234256.4EnsemblENSP00000234256.38MANE Select
NM_001193493.2RefSeqNP_001180422.14Standard
NM_001348406.2RefSeqNP_001335335.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Argininemia
  • Citrullinemia Type I
  • Carbamoyl Phosphate Synthetase Deficiency
  • Argininosuccinic Aciduria
  • Glucose-Alanine Cycle

Biological Process

  • amino acid transport
  • glutamine transport
  • L-alanine transport
  • L-cystine transport
  • proline transport

Molecular Function

  • chloride channel activity
  • amino acid transmembrane transporter activity
  • L-alanine transmembrane transporter activity
  • L-cystine transmembrane transporter activity
  • L-glutamine transmembrane transporter activity

Cellular Component

  • centrosome
  • microtubule organizing center
  • intermediate filament
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000234256
Coding exons
8
Length
35389
Individuals with no LoFs
125718
Homozygous LoFs
0
Heterozygous LoFs
29
Defined
125747
p
0.000115
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.732193040.7210.00001653366
Missense (PolyPhen)121166.480.726811859
Synonymous0.4861281350.9470.000008121179
Loss of Function2.62516.50.3037.99e-7200

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000190.00019rare
South Asian0.0000980.000098rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transporter for alanine, serine, cysteine, and threonine. Exhibits sodium dependence. {ECO:0000269|PubMed:26041762}.;

Recessive Scores

pRec
0.173

Intolerance Scores

LoFtool
0.519
RVIS EVS
-0.11
RVIS percentile EVS
45.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.618

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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