Submissions for variant NM_007118.4(TRIO):c.8834C>T (p.Thr2945Met)

gnomAD frequency: 0.00002  dbSNP: rs574639687

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001270888	SCV001451668	uncertain significance	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2019-08-08	criteria provided, single submitter	clinical testing	The TRIO c.8834C>T (p.Thr2945Met) variant is a missense variant that has been previously reported as a de novo occurrence in an individual with Lennox-Gastaut syndrome (Epi4K Consortium 2013). This variant is reported at a frequency of 0.000039 in the European (non-Finnish) population of the Genome Aggregation Database. The p.Thr2945Met variant affects the protein kinase domain of TRIO. While protein interactions mediated by this domain have been described (Medley et al. 2003), the involvement of this domain in the disease pathway underlying TRIO-related intellectual disability is unclear, since reduced RAC1 activation has been implicated, and RAC1 regulation is mediated through the first Dbl-homology-Pleckstrin-homology Rho-guanine exchange factor domain. In addition, the TRIO isoform that is most highly expressed in the brain does not include the kinase domain (Katrancha et al. 2017). In silico tools also differ in their predictions of the effect of this variant. Based on the available evidence and the application of the ACMG criteria, the p.Thr2945Met variant is classified as a variant of uncertain significance for TRIO-related intellectual disability.