ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23020937 Rauch et al. (2012) detected a de novo frameshift variant (c.452 delT/p.Leu151Argfs?35) in a patient with non-syndromic intellectual disability.
25865495 Carvill et al. (2015) did targeted resequencing on 644 individuals with epileptic encephalopathies which led to the identification of six SLC6A1 mutations in seven individuals. The mutations included two de novo truncating variants (c.1369_1370 delGG/p.Gly457Hisfs?10 and c.578G>A/p.Trp193?) and four missense alterations ( c.131G>A (p.Arg44Gln), de novo; c.889G>A (p.Gly297Arg), de novo; c.1000G>C (p.Ala334Pro)(maternal 9% mosaic and c.863C>T (p.Ala288Val) (inherited from affected mother). The authors believed all these mutations most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. In addition a small de novo deletion involving SLC6A11 and exon 1 of SLC6A1 was detected in a patient with seizure and intellectual disability.
28849312 Zech M et al. (2017) did WES on a cohort of nine patients with varied combined and/or complex dystonic presentation and identified a de novo splicing mutation c.1079-1G>A/p.Gly360ValfsX14 in patient with a diagnosis of adolescence-onset complex dystonia Epilepsy, intellectual disability.

Haploinsufficiency phenotype comments:

From the above 3 publications, 4 de novo null variants (3 frameshift, 1 nonsense) and more than 10 missense variants (some are also de novo) in SLC6A1, had been reported in patients presented with neurodevelopmental disorders, with epilepsy, autism and intellectual disability as frequent features. Although no functional study was performed, these variants were predicted to cause loss of function. In addition to the deletion involving part of SLC6A1 (as well as SLC6A11) reported by Carvill et al., Dikow et al. (2014) did a case report and literature review of patients with proximal 3p25.3 microdeletions and showing a consistent non-3p- syndrome (3p25.3 distal microdeletions) phenotype characterized by ID, epilepsy/EEG abnormalities, poor speech, ataxia and stereotypic hand movements. They proposed a smallest region of overlap (SRO) among these microdeletions that contains only two genes: SLC6A 11 and SLC6A1 (PubMed ID 25256099). Sajan et al. (2018) (PMID: 27171548) also reported a de novo 680kb deletion (chr3:10923941-11606490, hg19) that involves 6 genes including SLC6A 11 and SLC6A1 in a patient with myoclonic epilepsy. Johannesen et al. (2018) (PMID:29315614) did targeted sequencing of SLC6A1 in 24 patients and 6 family members affected with patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID) and identified 4 de novo truncating variants (C.1600C>T p.Gln534Ter, c.1342A>T p.Lys448Ter, ?.987C>? p.Cys329Ter & c.104dupA p.Lys36GluFsTer171), besides more than 20 missense variants (majority of which were also de novo). No null variants are reported in ExAC database, the pLI of SLC6A1 is 1. Sufficient evidence support the haploinsufficiency of SLC6A1 gene.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity