16-56192353-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_020988.3(GNAO1):c.118G>C(p.Gly40Arg) variant causes a missense, splice region 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. 15/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAO1 NM_020988.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.59

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 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_020988.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56192574-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GNAO1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-56192353-G-C is Pathogenic according to our data. Variant chr16-56192353-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287466.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}. Variant chr16-56192353-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/9	ENST00000262493.12
GNAO1	NM_138736.3	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/8
GNAO1	XR_007064866.1	n.865G>C		splice_region_variant, non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epileptic encephalopathy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Feb 25, 2020	de novo variant, previously described in the literature, absent from gnomAD. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2017	The c.118 G>C variant in the GNAO1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.118 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that the c.118 G>C change may destroy the natural splice acceptor site in intron 1. However, in the absence of RNA/functional studies, the actual effect of the c.118 G>C change in this individual is unknown. If c.118 G>C does not alter splicing, it will result in the G40R missense change. The G40R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same amino acid (G40R) resulting in a different nucleotide change (c.118 G>A) has been reported previously as a de novo, heterozygous change, in a female child with infantile-onset epilepsy, developmental delay and hypotonia (Law et al., 2015). Additionally, a missense variant in a nearby residue (G42R) has also been reported in the Human Gene Mutation Database in association with a GNAO2-related disorder (Stenson et al., 2014). These variants support the functional importance of this region of the protein. We interpret c.118 G>C as a pathogenic variant -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2018

A different variant affecting this nucleotide (c.118G>A)resulting in the same protein affect (p.G40R) has been determined to be pathogenic (PMID: 26485252, 28747448, 28817111). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported to be de novo in individuals affected with GNAO1 related disease; however, paternity was not confirmed (PMID: 28357411, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 40 of the GNAO1 protein (p.Gly40Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 1 of the GNAO1 coding sequence, which is part of the consensus splice site for this exon. -

Developmental and epileptic encephalopathy, 17 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pediatric Department, Peking University First Hospital

Feb 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H;.;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.4	D;.;.;D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.95
MutPred		0.90		Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.030		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: rs886041715; hg19: chr16-56226265;