Submissions for variant NM_020988.3(GNAO1):c.736G>A (p.Glu246Lys)

dbSNP: rs797044951

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190803	SCV000244244	pathogenic	Inborn genetic diseases	2014-06-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000254701	SCV000321739	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	Cells transfected with the E246K variant exhibited lower protein levels compared to wild-type, and functional studies demonstrated a gain-of-function effect for the E246K variant (PMID: 28747448); 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: 31076915, 27068059, 25356970, 26795593, 25966631, 28688840, 28628939, 29761117, 28668776, 33298085, 34122306, 28747448)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254701	SCV001446748	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814097	SCV001755297	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001808530	SCV002058168	pathogenic	Developmental and epileptic encephalopathy, 17	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: VCV000208777, PMID:25966631, PS1_S). A different missense change at the same codon (p.Glu246Gln, p.Glu246Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000689763, PMID:28357411, PMID:31216405, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.844, 3CNET: 0.848, PP3_P). A missense variant is a common mechanism associated with Epileptic encephalopathy (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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857676	SCV002241963	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNAO1 function (PMID: 28747448). 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: 208777). This missense change has been observed in individual(s) with neurodevelopmental disorder with involuntary movements (PMID: 27068059). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 246 of the GNAO1 protein (p.Glu246Lys).
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000490631	SCV002822904	pathogenic	Neurodevelopmental disorder with involuntary movements		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490631	SCV004801504	pathogenic	Neurodevelopmental disorder with involuntary movements	2020-10-05	criteria provided, single submitter	clinical testing	The GNAO1 c.736G>A p.(Glu246Lys) missense variant has been identified in individuals with a phenotype consistent with neurodevelopmental disorder with involuntary movements, in whom the variant occurred in a de novo state in at least four individuals (Feng et al. 2018).This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies demonstrated when the p.Glu246Lys variant was expressed in HEK293T cells, it exhibited increased potency for α2A AR–mediated cAMP inhibition consistent with a gain-of-function mechanism (Feng et al. 2017). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. The variant was identified in a de novo state in the proband. Based on the collective evidence the c.736G>A p.(Glu246Lys) variant is classified as pathogenic for neurodevelopmental disorder with involuntary movements.
Illumina Laboratory Services, Illumina	RCV003996903	SCV004814153	pathogenic	GNAO1-related developmental delay-seizures-movement disorder spectrum	2020-05-10	criteria provided, single submitter	clinical testing	The GNAO1 c.736G>A p.(Glu246Lys) missense variant has been identified in individuals with a phenotype consistent with GNAO1-related developmental delay-seizures-movement disorder spectrum. The variant occurred de novo in at least four of the individuals (Feng et al. 2018). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies found that when the p.Glu246Lys variant expressed in HEK293T cells, it exhibited increased potency for alpha-2A AR-mediated cAMP inhibition consistent with a gain-of-function mechanism (Feng et al. 2017). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. The variant was identified in a de novo state in the proband. Based on the collective evidence the c.736G>A p.(Glu246Lys) variant is classified as pathogenic for GNAO1-related developmental delay-seizures-movement disorder spectrum.
OMIM	RCV000490631	SCV000579321	pathogenic	Neurodevelopmental disorder with involuntary movements	2017-06-02	no assertion criteria provided	literature only
Pediatric Department, Peking University First Hospital	RCV001580372	SCV001486219	pathogenic	Developmental delay	2021-02-03	no assertion criteria provided	clinical testing