rs797044951
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000262493.12(GNAO1):c.736G>A(p.Glu246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E246G) has been classified as Pathogenic.
Frequency
Consequence
ENST00000262493.12 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNAO1 | NM_020988.3 | c.736G>A | p.Glu246Lys | missense_variant | 7/9 | ENST00000262493.12 | NP_066268.1 | |
GNAO1 | XM_011523003.4 | c.610G>A | p.Glu204Lys | missense_variant | 7/9 | XP_011521305.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNAO1 | ENST00000262493.12 | c.736G>A | p.Glu246Lys | missense_variant | 7/9 | 1 | NM_020988.3 | ENSP00000262493 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with involuntary movements Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 05, 2020 | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 26, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Developmental delay Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Pediatric Department, Peking University First Hospital | Feb 03, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2014 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | 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). - |
GNAO1-related developmental delay-seizures-movement disorder spectrum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 10, 2020 | 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. - |
Abnormality of the nervous system Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Developmental and epileptic encephalopathy, 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at