ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
29100089 Kury et al describe 12 de novo variants in CAMK2A identified through clinical exome sequencing in 14 individuals. Four of these variants were predicted loss-of-function changes (one frameshift and three splice site changes). The frameshift variant is of unknown inheritance (no paternal sample). The splice site changes were predicted by in silico and in vitro assessments to be damaging, though one was a +2 duplication. Virtually all affected variant positions were highly conserved and have no alternate allele in population genomics databases. Most pathogenic variants are sequestered in the kinase domain and many of the reported missense changes led to an unstable protein, causing a reduction in its levels. CAMK2A-associated phenotype includes intellectual disability, behavioral abnormalities, and delayed speech with variable presentation of epilepsy, visual impairment, and mild dysmorphic features. Camk2a knock-out mouse shows impaired hippocampus-dependent learning and hippocampal synaptic plasticity. The authors note that functional studies on missense variants sometimes indicate a loss of function mechanism, and other times support a gain of function mechanism.
29560374 Three de novo variants in CAMK2A identified through exome sequencing and shown to have a loss-of-function effect. One was a splicing mutation demonstrated to cause skipping of a coding exon through a mini gene assay. RT-PCR showed 3 aberrant transcripts, 2 fs and 1 in-frame deletion of most of regulatory segment that mediates autoinhibition. The missense variants were shown using a structural prediction model to adversely affect the interaction of the kinase domain and the segment that controls the auto-inhibition of its kinase activity.

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.