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

Genomes: not found (cov: 33)

Consequence

GNAO1
ENST00000262493.12 missense

Scores

16
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
GNAO1 (HGNC:4389): (G protein subunit alpha o1) The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 23 ACMG points.

PS1
Transcript ENST00000262493.12 (GNAO1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1701291
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000262493.12
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-56351396-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689763.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAO1. . Gene score misZ 3.1919 (greater than the threshold 3.09). Trascript score misZ 4.549 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 16-56351396-G-A is Pathogenic according to our data. Variant chr16-56351396-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56351396-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-56351396-G-A is described in Lovd as [Pathogenic]. Variant chr16-56351396-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNAO1NM_020988.3 linkuse as main transcriptc.736G>A p.Glu246Lys missense_variant 7/9 ENST00000262493.12 NP_066268.1
GNAO1XM_011523003.4 linkuse as main transcriptc.610G>A p.Glu204Lys missense_variant 7/9 XP_011521305.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNAO1ENST00000262493.12 linkuse as main transcriptc.736G>A p.Glu246Lys missense_variant 7/91 NM_020988.3 ENSP00000262493 P1P09471-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with involuntary movements Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 02, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn-- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 05, 2020The 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 submitterclinical testingGeneDxDec 26, 2023Cells 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 submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Developmental delay Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPediatric Department, Peking University First HospitalFeb 03, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2014- -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022For 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 submitterclinical testingIllumina Laboratory Services, IlluminaMay 10, 2020The 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 submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
Developmental and epileptic encephalopathy, 17 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
D;D;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H;H;.;.;.
MutationTaster
Benign
1.0
D
PROVEAN
Uncertain
-3.8
D;.;.;.;.
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;.;.;.;.
Polyphen
1.0
D;D;.;.;.
Vest4
0.93
MutPred
0.90
Gain of ubiquitination at E246 (P = 0.023);Gain of ubiquitination at E246 (P = 0.023);.;.;.;
MVP
0.97
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797044951; hg19: chr16-56385308; API