ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.