SLC1A3

Inheritance Pattern: AD

Disease ID:MONDO:0012982

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012982

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0012982

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012982

Submitter: ClinGen

SLC1A3, encoding glial excitatory amino acid transporter 1 (EAAT1), was first reported in relation to autosomal dominant episodic ataxia, type 6 in 2005 (Jen et al., PMID: 16116111). This disease entity represents a spectrum of disorder, ranging from episodic migraine and hemiparesis to the more severe form characterized by ataxia, slurred speech, and seizures. Eight unique variants, most of which are missense, 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 eight probands in eight publications (PMIDs: 27829685, 16116111, 29062094, 19139306, 29208948, 29066757, 32754645, 25497598). Functional studies performed on the seven observed missense variants demonstrate several possible pathogenic mechanisms depending on the mutation, with the most severe variants (p.M128R, p.P290R, and p.T318A) causing a gain-of-function altered glutamate transport and anion channels. Other variants usually cause increased amounts of transcribed protein for similar effectiveness to WT, indicating a haploinsufficency defect in glutamate uptake and anion currents (Chivukula et al., PMID: 32741053). Of note, this gene has also been implicated in Tourette syndrome and ADHD/Autism susceptibility (PMIDs: 21233784, 27296938). These will be assessed separately This gene-disease association is supported primarily by a knock-in mouse model of the most characterized variant P290R which recapitulated the phenotypes of the human disorder. Several instances of functional evidence have also been characterized, with a knock-out model organism demonstrating altered glutamate transport and motor/neurological phenotypes as well as a thorough functional characterization of six missense variants in HEK293 cells. In summary, SLC1A3 is definitively associated with autosomal dominant episodic ataxia. Although more published genetic evidence would allow for further characterization, the large amount of experimental data available provides important evidence towards its pathogenicity.

Inheritance Pattern: Unknown

Disease ID:MONDO:0012982

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.