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
25138099 Kuechler et al. (2014) performed whole exome sequencing (trio analysis) on a cohort of 301 patients with intellectual disability and identified de novo intragenic variants in SET domain-containing 5 (SETD5) in two unrelated female patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splite-donor site. Both intragenic variants were shown to undergo nonsense mediated decay, consistent with a loss-of-function and haploinsufficiency. Genomic microarray analysis of the same cohort identified additional de novo nonfocal microdeletions encompassing the SETD5 gene in 4 unrelated patients (6 total). In addition to ID, all patients with SETD5 alterations in this study were reported to have similar facial dysmorphisms.
24680889 Grozeva et al. (2014) sequenced a cohort of 996 patients with moderate to severe ID by a targeted NGS approach and identified 7 unrelated male patients with de novo heterozygous frameshift or truncating mutations in SETD5. This reference was also reviewed in OMIM (see

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.