ClinVar Genomic variation as it relates to human health
NM_020988.3(GNAO1):c.626G>A (p.Arg209His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020988.3(GNAO1):c.626G>A (p.Arg209His)
Variation ID: 208677 Accession: VCV000208677.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56336763 (GRCh38) [ NCBI UCSC ] 16: 56370675 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 Feb 14, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020988.3:c.626G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066268.1:p.Arg209His missense NM_138736.3:c.626G>A NP_620073.2:p.Arg209His missense NC_000016.10:g.56336763G>A NC_000016.9:g.56370675G>A NG_042800.1:g.150425G>A - Protein change
- R209H
- Other names
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- Canonical SPDI
- NC_000016.10:56336762:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GNAO1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
480 | 520 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2016 | RCV000190691.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2022 | RCV000255659.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000490633.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV001065368.5 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321738.8
First in ClinVar: Oct 09, 2016 Last updated: Dec 17, 2022 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jun 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244132.7
First in ClinVar: Sep 14, 2015 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Hypertonia (present) , Spasticity (present) , Cerebellar ataxia (present) , Dysmetria (present) , Unsteady gait (present) , Intention tremor (present) , Feeding difficulties (present) , … (more)
Hypertonia (present) , Spasticity (present) , Cerebellar ataxia (present) , Dysmetria (present) , Unsteady gait (present) , Intention tremor (present) , Feeding difficulties (present) , Global developmental delay (present) , Drooling (present) , Oculomotor apraxia (present) , Prominent forehead (present) , Synophrys (present) , Thick eyebrow (present) , Epicanthus (present) , Telecanthus (present) , Midface retrusion (present) , Wide nasal bridge (present) , Micrognathia (present) , High, narrow palate (present) , Dental crowding (present) , Low-set, posteriorly rotated ears (present) , Hirsutism (present) , Muscular hypotonia (present) , Vertigo (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Mar 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with involuntary movements
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150118.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with involuntary movements
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058662.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Broad distal phalanx of finger (present) , Esodeviation (present) , Curly eyelashes (present) , Aplasia cutis congenita (present) , Epicanthus (present) , Global developmental delay … (more)
Broad distal phalanx of finger (present) , Esodeviation (present) , Curly eyelashes (present) , Aplasia cutis congenita (present) , Epicanthus (present) , Global developmental delay (present) , Hypertelorism (present) , Generalized hypotonia (present) , Generalized hypotonia (present) , Low-set ears (present) , Macrocephaly at birth (present) , Macrocephaly (present) , Overgrowth (present) , Overlapping toe (present) , Thick hair (present) , Uplifted earlobe (present) (less)
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Pathogenic
(Jun 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024862.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001230324.3
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jun 02, 2017)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000579319.1
First in ClinVar: Jun 05, 2017 Last updated: Jun 05, 2017 |
Comment on evidence:
In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Kulkarni et al. (2016) identified a de novo heterozygous c.626G-A transition in exon 6 … (more)
In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Kulkarni et al. (2016) identified a de novo heterozygous c.626G-A transition in exon 6 of the GNAO1 gene, resulting in an arg209-to-his (R209H) substitution at a conserved residue in the highly conserved switch II region, which activates downstream effectors upon GTP binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in one of them. The mutation was filtered against the dbSNP and 1000 Genomes Project databases and was not found in the Exome Sequencing Project database. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. Using exome sequencing, Menke et al. (2016) identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed. In a 16-year-old boy with NEDIM, Ananth et al. (2016) identified a de novo heterozygous R209H mutation in the GNAO1 gene. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Impact of clinical exomes in neurodevelopmental and neurometabolic disorders. | Evers C | Molecular genetics and metabolism | 2017 | PMID: 28688840 |
GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome. | Danti FR | Neurology. Genetics | 2017 | PMID: 28357411 |
Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. | Parrini E | Human mutation | 2017 | PMID: 27864847 |
Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder. | Menke LA | Journal of child neurology | 2016 | PMID: 27625011 |
Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder. | Ananth AL | Pediatric neurology | 2016 | PMID: 27068059 |
Progressive Movement Disorder in Brothers Carrying a GNAO1 Mutation Responsive to Deep Brain Stimulation. | Kulkarni N | Journal of child neurology | 2016 | PMID: 26060304 |
Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. | Saitsu H | European journal of human genetics : EJHG | 2016 | PMID: 25966631 |
Text-mined citations for rs797044878 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.