ClinVar Miner

Submissions for variant NM_020988.3(GNAO1):c.118G>C (p.Gly40Arg) (rs886041715)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000486165 SCV000341248 uncertain significance not provided 2016-04-15 criteria provided, single submitter clinical testing
GeneDx RCV000486165 SCV000573953 pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing The c.118 G>C variant in the GNAO1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.118 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that the c.118 G>C change may destroy the natural splice acceptor site in intron 1. However, in the absence of RNA/functional studies, the actual effect of the c.118 G>C change in this individual is unknown. If c.118 G>C does not alter splicing, it will result in the G40R missense change. The G40R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same amino acid (G40R) resulting in a different nucleotide change (c.118 G>A) has been reported previously as a de novo, heterozygous change, in a female child with infantile-onset epilepsy, developmental delay and hypotonia (Law et al., 2015). Additionally, a missense variant in a nearby residue (G42R) has also been reported in the Human Gene Mutation Database in association with a GNAO2-related disorder (Stenson et al., 2014). These variants support the functional importance of this region of the protein. We interpret c.118 G>C as a pathogenic variant
Invitae RCV000702017 SCV000830844 pathogenic Early infantile epileptic encephalopathy 2018-08-01 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with GNAO1 related disease; however, paternity was not confirmed (PMID: 28357411, Invitae). 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"). 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. 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.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001003610 SCV001162778 pathogenic Epileptic encephalopathy 2020-02-25 criteria provided, single submitter clinical testing de novo variant, previously described in the literature, absent from gnomAD.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003610 SCV001162021 likely pathogenic Epileptic encephalopathy no assertion criteria provided research

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