16-56336763-G-T

Position:

• chr16-56336763-G-T

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>T​(p.Arg209Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely 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)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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, 0.987
• PP5: Variant 16-56336763-G-T is Pathogenic according to our data. Variant chr16-56336763-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431699.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>T	p.Arg209Leu	missense_variant	6/9	ENST00000262493.12
GNAO1	NM_138736.3	c.626G>T	p.Arg209Leu	missense_variant	6/8
GNAO1	XM_011523003.4	c.500G>T	p.Arg167Leu	missense_variant	6/9
GNAO1	XR_007064866.1	n.1373G>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.626G>T	p.Arg209Leu	missense_variant	6/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2018

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the p.Arg209 amino acid residue in GNAO1 have been observed in affected individuals (PMID: 28357411, 25966631, 28688840, 27864847, 27068059, 26060304, 27625011). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual with developmental delay and a movement disorder (PMID: 27625011). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 209 of the GNAO1 protein (p.Arg209Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Dec 22, 2020

- -

Developmental and epileptic encephalopathy, 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

TIDEX, University of British Columbia

-

- -

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	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	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	-6.6	D;.;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.95
MutPred		0.92		Loss of disorder (P = 0.0259);Loss of disorder (P = 0.0259);Loss of disorder (P = 0.0259);.;
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
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;