NM_020988.3(GNAO1):c.680C>T (p.Ala227Val) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000694174.8

Allele description [Variation Report for NM_020988.3(GNAO1):c.680C>T (p.Ala227Val)]

NM_020988.3(GNAO1):c.680C>T (p.Ala227Val)

Gene:

GNAO1:G protein subunit alpha o1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q13

Genomic location:

Preferred name:

NM_020988.3(GNAO1):c.680C>T (p.Ala227Val)

HGVS:

NC_000016.10:g.56336817C>T
NG_042800.1:g.150479C>T
NM_020988.3:c.680C>TMANE SELECT
NM_138736.3:c.680C>T
NP_066268.1:p.Ala227Val
NP_620073.2:p.Ala227Val
NC_000016.9:g.56370729C>T
NM_020988.1:c.680C>T
NM_020988.2:c.680C>T
P09471:p.Ala227Val

Protein change:

A227V

Links:

UniProtKB: P09471#VAR_077338

Molecular consequence:

NM_020988.3:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_138736.3:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:: Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000822605	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25966631, 28747448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000822605

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 27, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.

Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N.

Eur J Hum Genet. 2016 Jan;24(1):129-34. doi: 10.1038/ejhg.2015.92. Epub 2015 May 13.

PubMed [citation]

PMID:: 25966631
PMCID:: PMC4795232

Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.

Feng H, Sjögren B, Karaj B, Shaw V, Gezer A, Neubig RR.

Neurology. 2017 Aug 22;89(8):762-770. doi: 10.1212/WNL.0000000000004262. Epub 2017 Jul 26.

PubMed [citation]

PMID:: 28747448
PMCID:: PMC5580866

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000822605.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. ClinVar contains an entry for this variant (Variation ID: 211088). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 25966631). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 227 of the GNAO1 protein (p.Ala227Val). Experimental studies have shown that this missense change affects GNAO1 function (PMID: 28747448). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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