16-56336763-G-A

Position:

• chr16-56336763-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_020988.3(GNAO1):​c.626G>A​(p.Arg209His) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R209G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 19 ACMG points.

• 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 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 chr16-56336762-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.97
• PP5: Variant 16-56336763-G-A is Pathogenic according to our data. Variant chr16-56336763-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.626G>A	p.Arg209His	missense_variant	6/9	ENST00000262493.12
GNAO1	NM_138736.3	c.626G>A	p.Arg209His	missense_variant	6/8
GNAO1	XM_011523003.4	c.500G>A	p.Arg167His	missense_variant	6/9
GNAO1	XR_007064866.1	n.1373G>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.626G>A	p.Arg209His	missense_variant	6/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726800

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with involuntary movements Pathogenic:3

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: VCV000208677, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265350,VCV000431699, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.914, 3CNET: 0.917, PP3_P). A missense variant is a common mechanism associated with Neurodevelopmental disorder with involuntary movements (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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 20, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 02, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	Published functional studies demonstrate that R209H knock-in mice display similar phenotype to patients harboring this variant and respond to risperidone, an approved pharmacological agent (Larrivee et al., 2020); 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: 31907305, 26060304, 27625011, 27068059, 30682224, 33298085, 33084218, 33098801, 33258288, 28688840, 28357411, 27864847, 25966631, 28747448, 30838255, 33619735) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2016

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GNAO1 protein (p.Arg209His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurodevelopmental disorder with involuntary movements (NEDIM) (PMID: 26060304, 27068059, 27625011). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208677). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg209 amino acid residue in GNAO1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25966631, 27625011, 27864847, 28357411, 28688840). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.87		Loss of MoRF binding (P = 0.0561);Loss of MoRF binding (P = 0.0561);Loss of MoRF binding (P = 0.0561);.;
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.99

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

Other links and lift over

dbSNP: rs797044878; hg19: chr16-56370675;