Genetic Variant GNAO1:p.Arg209Cys (chr16-56336762-C-T) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_020988.3(GNAO1):c.625C>T(p.Arg209Cys) variant causes a missense change. 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Consequence

GNAO1
NM_020988.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 4.91

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]

GNAO1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 4.549 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 16-56336762-C-T is Pathogenic according to our data. 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. Variant chr16-56336762-C-T is described in Lovd as [Pathogenic]. Variant chr16-56336762-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3 link	c.625C>T	p.Arg209Cys	missense_variant	Exon 6 of 9	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 link	c.625C>T	p.Arg209Cys	missense_variant	Exon 6 of 8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XM_011523003.4 link	c.499C>T	p.Arg167Cys	missense_variant	Exon 6 of 9		XP_011521305.1
GNAO1	XR_007064866.1 link	n.1372C>T		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12 link	c.625C>T	p.Arg209Cys	missense_variant	Exon 6 of 9	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with involuntary movements

Pathogenic:6

Dec 03, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GNAO1 c.625 C>T p.(Arg209Cys) missense variant has been reported in four studies, in which it is found in a heterozygous state in a total of six individuals with a phenotype consistent with neurodevelopmental disorder with involuntary movements (Saitsu et al. 2016; Danti et al. 2017; Koy et al. 2018; Waak et al. 2018). In each case the variant was found to arise de novo. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Arg209Cys is located at a highly conserved residue. Four other variants affecting the Arg209 residue have been described, all of which are associated with a prominent movement disorder phenotype, with a low prevalence of epilepsy, Indeed, thirty percent of GNAO1 pathogenic missense variants are reported to be localised at the Arg209 residue (Tommaso et al. 2018). In silico homology modelling predicts that the Arg209 residue is required for the stability of the GNAO1 heterocomplex in the GTP bound form, however the GNAO1 p.(Arg209Cys) variant did not affect protein activity when expressed in a heterologous cell culture system (Saitsu et al. 2016; Feng et al. 2017). The variant was identified in a de novo state in the proband. Based on the available evidence, the c.625 C>T p.(Arg209Cys) variant is classified as pathogenic for GNAO1-related movement disorder. -

Jan 18, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 13, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously in multiple individuals with intellectual disability, developmental delay, and movement disorders [PMID 25966631, 28357411, 28688840, 27864847, 27916449] -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jan 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 28688840, 28357411, 25966631, 27864847, 28747448, 28628939, 27916449, 25533962, 30682224, 28191890, 28668776, 30642806, 31190250, 32581362, 33446253, 33098801, 33358199, 33619735) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Oct 07, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Nov 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 209 of the GNAO1 protein (p.Arg209Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25966631, 27864847, 28357411, 28688840). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265350). 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: 26060304, 27068059, 27625011). 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. -

Movement disorder

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Developmental and epileptic encephalopathy, 17

Pathogenic:1

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 25533962, 28688840 PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg209Leu and Arg209His) has been reported as pathogenic (VCV000431699.1, VCV000208677.6, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.888, 3Cnet: 0.960, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

GNAO1-related disorder

Pathogenic:1

Apr 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GNAO1 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Cys. This variant has been reported as de novo in multiple individuals with intellectual disability, developmental delay, and movement disorders (Saitsu. 2016. PubMed ID: 25966631; Brunet. 2021. PubMed ID: 33619735; Evers. 2017. PubMed ID: 28688840; Kelly. 2019. PubMed ID: 30682224; Malaquias. 2019. PubMed ID: 31190250). 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. -

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

Other:1

Genomeconnect - The Bow Foundation (GNAO1)

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 04-23-2019 by OHSU Knight Diagnostic Laboratories. GenomeConnect-GNAO1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;H;H;.

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.5

D;.;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;D;D;.

Vest4

0.95

MutPred

0.90

Loss of disorder (P = 0.01);Loss of disorder (P = 0.01);Loss of disorder (P = 0.01);.;

MVP

0.97

MPC

3.2

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over