ClinVar

Description

A different variant affecting this nucleotide (c.118G>A)resulting in the same protein affect (p.G40R) has been determined to be pathogenic (PMID: 26485252, 28747448, 28817111). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported to be de novo in individuals affected with GNAO1 related disease; however, paternity was not confirmed (PMID: 28357411, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 40 of the GNAO1 protein (p.Gly40Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 1 of the GNAO1 coding sequence, which is part of the consensus splice site for this exon.