ClinVar

In 3 unrelated patients with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.239T-C transition (c.239T-C, NM_002074.4) in exon 6 of the GNB1 gene, resulting in an ile80-to-thr (I80T) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the Exome Sequencing Project (March 2013) and ExAC (January 2015) databases. The substitution occurs along the GNB1 protein surface that interacts with G-alpha subunits and downstream effectors. Yoda et al. (2015) had identified somatic I80T variants in association with hematologic transformation, including myelodysplastic syndrome (MDS; 614286) and chronic lymphocytic leukemia (CLL; 151400). I80T was demonstrated to have reduced binding to almost all G-alpha subunits, which conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. Petrovski et al. (2016) noted that I80T has been reported in the ExAC browser as a low-confidence variant, but suggested that it may be a technical artifact or a postzygotic mutation. Functional studies of the variant and studies of patient cells were not performed by Petrovski et al. (2016). See 139380.0003 for another mutation affecting this residue.

Hemati et al. (2018) identified de novo heterozygosity for the I80T mutation in the GNB1 gene in 8 patients with MRD42.