ClinGen Dosage Sensitivity Curation Page

SLC6A18

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
32487729 Rausell et al. (2020) suggested that this gene is dosage sensitivity unlikely because it had at least one homozygous LoF variant present in >1% of the gnomAD population. Examples of homozygous LoF or likely LoF variants in this gene in gnomAD include p.Lys20SerfsTer10 (1 homozygous individual), p.Tyr319Ter (18840 homozygous individuals), and c.975-2A>T (1 homozygous individual).
22344438 MacArthur et al. (2012) suggested that this gene is dosage sensitivity unlikely because it had at least one homozygous LoF variant present at >5% of the 1000 Genomes Project database.
28406212 Saleheen et al. (2017) identified 1 adult individual in a Pakistani population with a homozygous LoF variants in this gene. The individuals were originally recruited for a study evaluating risk of myocardial infarction. Individuals within that study found to have homozygous predicted LOF variants were phenotyped for ?more than 200 biochemical and disease traits?.
25807282 Sulem et al. (2015) identified 18557 individuals in an Icelandic population with a homozygous LoF variants in this gene. This population was participating in a variety of disease projects and the researchers pulled this population to investigate how often homozygous LoF variants were found in this population.
32461654 Karczewski et al. (2020) identifies 443,769 high confidence loss of function variants in the Genome Aggregation Database (gnomAD) population including these LoF and likely LoF variants (p.Lys20SerfsTer10, p.Tyr319Ter, and c.975-2A>T). Several methods were used to identify these genes including manual curation and utilizing LOEUF scores.

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.