ClinVar Genomic variation as it relates to human health
NM_020988.3(GNAO1):c.625C>T (p.Arg209Cys)
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
-
NM_020988.3(GNAO1):c.625C>T (p.Arg209Cys)
Variation ID: 265350 Accession: VCV000265350.54
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q13 16: 56370674 (GRCh37) [ NCBI UCSC ] 16: 56336762 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 5, 2017 May 12, 2024 Nov 20, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_020988.3:c.625C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066268.1:p.Arg209Cys missense NM_138736.3:c.625C>T NP_620073.2:p.Arg209Cys missense NC_000016.10:g.56336762C>T NC_000016.9:g.56370674C>T NG_042800.1:g.150424C>T P09471:p.Arg209Cys - Protein change
- R209C
- Other names
- -
- Canonical SPDI
- NC_000016.10:56336761:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
GNAO1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
468 | 506 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2022 | RCV000256155.25 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2020 | RCV000490628.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 20, 2023 | RCV000475848.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 7, 2015 | RCV000622320.5 | |
Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003612.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 2, 2021 | RCV001775107.4 | |
GNAO1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2023 | RCV003401217.4 |
Submissions - Germline
Classification
Help
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
Help
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446487.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Dyskinesia (present) , Global developmental delay (present)
Sex: male
|
|
Pathogenic
(Jan 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with involuntary movements
Affected status: yes
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449009.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Generalized hypotonia (present) , Muscular hypotonia (present) , Dystonia (present) , Choreoathetosis (present) , Delayed speech and language development (present) , Global developmental delay (present) … (more)
Generalized hypotonia (present) , Muscular hypotonia (present) , Dystonia (present) , Choreoathetosis (present) , Delayed speech and language development (present) , Global developmental delay (present) , Short stature (present) , Myopathy (present) , Cerebral palsy (present) (less)
Sex: male
|
|
Pathogenic
(Aug 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with involuntary movements
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001529933.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously in multiple individuals with intellectual disability, developmental … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously in multiple individuals with intellectual disability, developmental delay, and movement disorders [PMID 25966631, 28357411, 28688840, 27864847, 27916449] (less)
|
|
Pathogenic
(Aug 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with involuntary movements
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149794.2
First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Choreoathetosis (present) , Cerebral palsy (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Cerebral palsy (present) , Dyskinesia (present) , Chorea (present) , Dystonic disorder (present)
|
|
Pathogenic
(Oct 07, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740968.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Truncal ataxia (present) , Poor fine motor coordination (present) , Dysmetria (present) , Drooling (present) , Absent speech (present) , Seizures (present) , Abnormal muscle … (more)
Truncal ataxia (present) , Poor fine motor coordination (present) , Dysmetria (present) , Drooling (present) , Absent speech (present) , Seizures (present) , Abnormal muscle tone (present) , Upper limb hypertonia (present) , Lower limb hypertonia (present) , Abnormality of the Achilles tendon (present) , Limited elbow extension (present) , Gait ataxia (present) , Decreased fetal movement (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
|
|
Pathogenic
(Jan 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322148.9
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
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; … (more)
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: 28688840, 28357411, 25966631, 27864847, 28747448, 28628939, 27916449, 25533962, 30682224, 28191890, 28668776, 30642806, 31190250, 32581362, 33446253, 33098801, 33358199, 33619735) (less)
|
|
Pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000550340.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 209 of the GNAO1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 209 of the GNAO1 protein (p.Arg209Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25966631, 27864847, 28357411, 28688840). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265350). 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: 26060304, 27068059, 27625011). 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)
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249674.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 17
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012060.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 25533962, 28688840 … (more)
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 25533962, 28688840 PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg209Leu and Arg209His) has been reported as pathogenic (VCV000431699.1, VCV000208677.6, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.888, 3Cnet: 0.960, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Generalized hypotonia (present) , Intellectual disability (present) , … (more)
Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Generalized hypotonia (present) , Intellectual disability (present) , Microcephaly (present) , Prominent nasal bridge (present) , Delayed speech and language development (present) , Protruding ear (present) , Short philtrum (present) , Abnormality of the dentition (present) (less)
|
|
Pathogenic
(Apr 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GNAO1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004111018.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GNAO1 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Cys. This variant has been reported as de novo in multiple individuals … (more)
The GNAO1 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Cys. This variant has been reported as de novo in multiple individuals with intellectual disability, developmental delay, and movement disorders (Saitsu. 2016. PubMed ID: 25966631; Brunet. 2021. PubMed ID: 33619735; Evers. 2017. PubMed ID: 28688840; Kelly. 2019. PubMed ID: 30682224; Malaquias. 2019. PubMed ID: 31190250). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with involuntary movements
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801492.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The GNAO1 c.625 C>T p.(Arg209Cys) missense variant has been reported in four studies, in which it is found in a heterozygous state in a total … (more)
The GNAO1 c.625 C>T p.(Arg209Cys) missense variant has been reported in four studies, in which it is found in a heterozygous state in a total of six individuals with a phenotype consistent with neurodevelopmental disorder with involuntary movements (Saitsu et al. 2016; Danti et al. 2017; Koy et al. 2018; Waak et al. 2018). In each case the variant was found to arise de novo. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Arg209Cys is located at a highly conserved residue. Four other variants affecting the Arg209 residue have been described, all of which are associated with a prominent movement disorder phenotype, with a low prevalence of epilepsy, Indeed, thirty percent of GNAO1 pathogenic missense variants are reported to be localised at the Arg209 residue (Tommaso et al. 2018). In silico homology modelling predicts that the Arg209 residue is required for the stability of the GNAO1 heterocomplex in the GTP bound form, however the GNAO1 p.(Arg209Cys) variant did not affect protein activity when expressed in a heterologous cell culture system (Saitsu et al. 2016; Feng et al. 2017). The variant was identified in a de novo state in the proband. Based on the available evidence, the c.625 C>T p.(Arg209Cys) variant is classified as pathogenic for GNAO1-related movement disorder. (less)
|
|
Pathogenic
(Jun 02, 2017)
|
no assertion criteria provided
Method: literature only
|
NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000579320.1
First in ClinVar: Jun 05, 2017 Last updated: Jun 05, 2017 |
Comment on evidence:
In an 18-year-old female with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Saitsu et al. (2016) identified a de novo heterozygous c.625C-T transition (c.625C-T, NM_020988.2) … (more)
In an 18-year-old female with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Saitsu et al. (2016) identified a de novo heterozygous c.625C-T transition (c.625C-T, NM_020988.2) in exon 6 of the GNAO1 gene, resulting in an arg209-to-cys (R209C) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would destabilize the G-alpha-containing complexes mainly in GTP-bound active state. Danti et al. (2017) identified a de novo heterozygous R209C mutation in 2 unrelated patients with NEDIM. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Danti et al. (2017) noted that the R209C mutation occurs in the switch II domain, which is important for regulation of downstream signaling. This residue (R209) is a mutational hotspot. (less)
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Movement disorder
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162023.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
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 |
A case of severe movement disorder with GNAO1 mutation responsive to topiramate. | Sakamoto S | Brain & development | 2017 | PMID: 27916449 |
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 |
Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. | Nakamura K | American journal of human genetics | 2013 | PMID: 23993195 |
click to load more click to collapse |
Text-mined citations for rs886039494 ...
HelpRecord last updated May 19, 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.