VCV000066115.67 - ClinVar

NM_020988.3(GNAO1):c.607G>A (p.Gly203Arg)

Germline

Classification

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.

(15)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020988.3(GNAO1):c.607G>A (p.Gly203Arg)

Variation ID: 66115 Accession: VCV000066115.67

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56336744 (GRCh38) [ NCBI UCSC ] 16: 56370656 (GRCh37) [ 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	Oct 9, 2016	Oct 20, 2024	Jun 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020988.3:c.607G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066268.1:p.Gly203Arg	missense
NM_138736.3:c.607G>A	NP_620073.2:p.Gly203Arg	missense
NC_000016.10:g.56336744G>A
NC_000016.9:g.56370656G>A
NG_042800.1:g.150406G>A
	P09471:p.Gly203Arg

... more HGVS ... less HGVS

Protein change

G203R

Other names

Canonical SPDI

NC_000016.10:56336743:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA214450 UniProtKB: P09471#VAR_070866 OMIM: 139311.0004 VarSome

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
Gene	OMIM	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	484	524

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.
Developmental and epileptic encephalopathy, 17	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 12, 2024	RCV000056408.37
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 2, 2022	RCV000255097.28
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2023	RCV000468248.12
Developmental and epileptic encephalopathy, 17 Neurodevelopmental disorder with involuntary movements	Pathogenic (2)	criteria provided, single submitter	Oct 31, 2018	RCV000762963.6
Rare genetic intellectual disability	Pathogenic (1)	no assertion criteria provided	-	RCV001256978.4
Microcephaly	Likely pathogenic (1)	no assertion criteria provided	-	RCV001252685.3
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814039.3
GNAO1-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 29, 2022	RCV003421966.5

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 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 17 Neurodevelopmental disorder with involuntary movements Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893404.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 17 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164237.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Sep 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 17 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580487.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS1, PS3, PM1, PM5, PM2_SUP, PP2, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (Aug 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GNAO1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004118582.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The GNAO1 c.607G>A variant is predicted to result in the amino acid substitution p.Gly203Arg. This is a recurrent de novo variant reported in individuals with … (more) The GNAO1 c.607G>A variant is predicted to result in the amino acid substitution p.Gly203Arg. This is a recurrent de novo variant reported in individuals with epileptic encephalopathy (Table 1, Nakamura et al. 2013. PubMed ID: 23993195; Arya et al. 2017. PubMed ID: 28202424; Table 1A, Fernández-Marmiesse et al. 2019. PubMed ID: 31780880). 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 (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826483.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jul 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000550342.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 23993195‚ 25966631‚ 26060304‚ 27072799‚ 28202424‚ 28747448 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the GNAO1 protein (p.Gly203Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the GNAO1 protein (p.Gly203Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Ohtahara syndrome, early infantile epileptic encephalopathy, and movement disorder (PMID: 23993195, 25966631, 26060304, 27072799, 28202424). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66115). 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. Experimental studies have shown that this missense change affects GNAO1 function (PMID: 28747448). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 08, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Developmental and epileptic encephalopathy, 17 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680246.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: de novo	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755204.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jan 19, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321737.9 First in ClinVar: Oct 09, 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: 25966631, 23993195, 28973083, 28628939, 28202424, 28688840, 29100083, 30642806, 31780880, 31737037, 34440436, 34122306, 33584783) (less)
Pathogenic (Jun 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 17 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005060838.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Clinical Features: Seizure (present) , Neonatal seizure (present)
Pathogenic (Nov 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249673.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rare genetic intellectual disability Affected status: yes Allele origin: de novo	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001433524.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020
Pathogenic (Sep 05, 2013)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000087517.4 First in ClinVar: Oct 20, 2013 Last updated: Oct 25, 2020	Publications: PubMed (3) PubMed: 23993195‚ 25966631‚ 28747448 Comment on evidence: In an 8-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo heterozygous c.607G-A transition in the GNAO1 … (more) In an 8-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo heterozygous c.607G-A transition in the GNAO1 gene, resulting in a gly203-to-arg (G203R) substitution in the highly conserved switch II region that is responsible for activation of downstream effectors. The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein localized normally to the cell periphery. However, electrophysiologic studies in N-type calcium channels indicated that the similar G203T mutant protein had impaired current inhibition after norepinephrine application compared to wildtype, suggesting that the mutation could hamper GNAO1-mediated signaling. The patient showed opisthotonic posturing at 7 months of age. She later developed severe chorea. In a 14-month-old girl with DEE17, Saitsu et al. (2016) identified a de novo heterozygous G203R mutation in the GNAO1 gene. 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. The patient developed seizures on the seventh day of life. She later developed severe chorea. Feng et al. (2017) found that the G203R variant resulted in a gain-of-function effect in a cAMP inhibition assay. The authors noted that the previously reported patients with this variant had a slightly different phenotype from classic DEE17, showing a prominent motor component. (less)
Pathogenic (Feb 03, 2021)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 17 Neurodevelopmental disorder with involuntary movements Affected status: yes Allele origin: de novo	Pediatric Department, Peking University First Hospital Accession: SCV001486218.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021	Publications: PubMed (4) PubMed: 23993195‚ 25966631‚ 28202424‚ 28628939 Age: 0-9 years Sex: male
Likely pathogenic (-)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	Microcephaly Affected status: yes Allele origin: de novo	Department of Pediatrics, Samsung Medical Center, Samsung Medical Center Accession: SCV001163828.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020
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Comment:

The GNAO1 c.607G>A variant is predicted to result in the amino acid substitution p.Gly203Arg. This is a recurrent de novo variant reported in individuals with epileptic encephalopathy (Table 1, Nakamura et al. 2013. PubMed ID: 23993195; Arya et al. 2017. PubMed ID: 28202424; Table 1A, Fernández-Marmiesse et al. 2019. PubMed ID: 31780880). 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.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the GNAO1 protein (p.Gly203Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Ohtahara syndrome, early infantile epileptic encephalopathy, and movement disorder (PMID: 23993195, 25966631, 26060304, 27072799, 28202424). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66115). 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. Experimental studies have shown that this missense change affects GNAO1 function (PMID: 28747448). For these reasons, this variant has been classified as Pathogenic.

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; This variant is associated with the following publications: (PMID: 25966631, 23993195, 28973083, 28628939, 28202424, 28688840, 29100083, 30642806, 31780880, 31737037, 34440436, 34122306, 33584783)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.	Feng H	Neurology	2017	PMID: 28747448
Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature.	Schorling DC	Neuropediatrics	2017	PMID: 28628939
GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype.	Arya R	Epileptic disorders : international epilepsy journal with videotape	2017	PMID: 28202424
GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females.	Marcé-Grau A	Orphanet journal of rare diseases	2016	PMID: 27072799
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
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

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_020988.3(GNAO1):c.607G>A (p.Gly203Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...