ClinVar

Description

The p.Ile80Thr variant in GNB1 has been reported in the literature as a de novo germline event in 10 individuals with clinical features of a neurodevelopmental disorder most commonly consisting of global developmental delays, hypotonia evolving to hypertonia and spasticity, abnormal vision, and epilepsy (Petrovski et al. 2016, Hemati et al. 2018) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 208722). Additionally, another missense variant at this same codon, p.Ile80Asn, has also been reported as a de novo germline event in several unrelated individuals with neurodevelopmental features (Petrovski et al. 2016). As a somatic event, the p.Ile80Thr variant has also been identified in individuals with hematologic, primarily B-cell, malignancies (Yoda et al. 2015) and in mice transplanted with p.Ile80Thr bone marrow (Yoda et al. 2015). The implications of these findings to individuals with germline variants remains to be determined (Petrovski et al. 2016, Hemati et al. 2018). The variant occurs at a critical residue, and functional studies support that variation at amino acid 80 impacts protein function (Ford et al. 1998, Yoda et al. 2015). Lastly, computational prediction tools and conservation analysis support that the p.Ile80Thr variant impacts protein function. In summary, this variant meets criteria to be classified as pathogenic for neurodevelopmental disorder in an autosomal dominant manner based upon case counts, de novo occurrence, location at a critical residue, a different pathogenic missense at the same position, functional evidence, and predicted impact on protein. ACMG/AMP Criteria applied: PS2_VeryStrong, PM5, PM1, PS3_Supporting, PP3