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
22542183 Iossifov et al. (2012) performed whole exome sequencing on a subset of 343 families from the Simons Simplex Collection in which there is one child on the autism spectrum and one (or more) normal siblings. They report a single de novo frameshift variant in a male that had been diagnosed with autism.
25284784 Dong et al. (2014) combined a family-based local realignment approach with empirically derived quality metric thresholds to look for de novo indels amongst a sample of previously analyzed whole exome sequencing data from 787 Simons Simplex Collection families. This group confirmed the de novo frameshift variant in RIMS1 first identified in Iossifov et al. (2012) (see PMID 1), and identified another de novo frameshift variant in a different male diagnosed with autism.
27824329 Wang et al. (2016) used single-molecule molecular inversion probes (smMIPs) to sequence the coding regions of 189 autism risk genes in a cohort of 1543 autism probands (1045 from trios) from the Autism Clinical and Genetics Resources in China (ACGC) group. They detected one de novo nonsense variant in an individual diagnosed with autism. In addition, the authors identified 2 inherited frameshift variants, 2 inherited nonsense variants, an inherited missense variant, and an additional frameshift variant of unknown inheritance in RIMS1.

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.