ClinVar Miner

Submissions for variant NM_020988.3(GNAO1):c.626G>A (p.Arg209His)

dbSNP: rs797044878
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190691 SCV000244132 pathogenic Inborn genetic diseases 2016-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000255659 SCV000321738 pathogenic not provided 2022-12-08 criteria provided, single submitter clinical testing Published functional studies demonstrate that R209H knock-in mice display similar phenotype to patients harboring this variant and respond to risperidone, an approved pharmacological agent (Larrivee et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31907305, 26060304, 27625011, 27068059, 30682224, 33298085, 33084218, 33098801, 33258288, 28688840, 28357411, 27864847, 25966631, 28747448, 30838255, 33619735)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000490633 SCV001150118 pathogenic Neurodevelopmental disorder with involuntary movements 2018-03-20 criteria provided, single submitter clinical testing
Invitae RCV001065368 SCV001230324 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GNAO1 protein (p.Arg209His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurodevelopmental disorder with involuntary movements (NEDIM) (PMID: 26060304, 27068059, 27625011). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAO1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg209 amino acid residue in GNAO1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25966631, 27625011, 27864847, 28357411, 28688840). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV000255659 SCV002024862 pathogenic not provided 2021-06-14 criteria provided, single submitter clinical testing
3billion RCV000490633 SCV002058662 pathogenic Neurodevelopmental disorder with involuntary movements 2022-01-03 criteria provided, single submitter clinical testing The variant has been previously reported as de novo in a similarly affected individual (PMID: 27068059, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000208677, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265350,VCV000431699, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.914, 3CNET: 0.917, PP3_P). A missense variant is a common mechanism associated with Neurodevelopmental disorder with involuntary movements (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000490633 SCV000579319 pathogenic Neurodevelopmental disorder with involuntary movements 2017-06-02 no assertion criteria provided literature only

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