16-56336744-G-A

Position:

• chr16-56336744-G-A

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000262493.12(GNAO1):​c.607G>A​(p.Gly203Arg) 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. 13/21 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. G203E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAO1 ENST00000262493.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.99

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]

ACMG classification

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 803257
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr16-56336745-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1319183.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, 0.989
• PP5: Variant 16-56336744-G-A is Pathogenic according to our data. Variant chr16-56336744-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56336744-G-A is described in Lovd as [Pathogenic]. Variant chr16-56336744-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-56336744-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.607G>A	p.Gly203Arg	missense_variant	6/9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.607G>A	p.Gly203Arg	missense_variant	6/8		NP_620073.2
GNAO1	XM_011523003.4	c.481G>A	p.Gly161Arg	missense_variant	6/9		XP_011521305.1
GNAO1	XR_007064866.1	n.1354G>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.607G>A	p.Gly203Arg	missense_variant	6/9	1	NM_020988.3	ENSP00000262493	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459738 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 17 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 12, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Department, Peking University First Hospital	Feb 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Microcephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

-

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2023

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. -

Rare genetic intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

GNAO1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.90
MutPred		0.93		Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);.;
MVP		0.95
MPC		2.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs587777057; hg19: chr16-56370656; COSMIC: COSV52613732; COSMIC: COSV52613732;