rs397514737

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_198904.4(GABRG2):c.968G>A(p.Arg323Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GABRG2
NM_198904.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.88

Publications

19 publications found

Variant links:

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRG2 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 74
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 8
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized epilepsy with febrile seizures plus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_198904.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-162149152-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 205549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant 5-162149153-G-A is Pathogenic according to our data. Variant chr5-162149153-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 60708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4 link	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2 link	c.968G>A	p.Arg323Gln	missense_variant	Exon 8 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251162

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 74

Pathogenic:2

Jul 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS4+PM6_VeryStrong+PS3_Moderate+PP2 -

not provided

Pathogenic:2

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); This variant is associated with the following publications: (PMID: 27864268, 27334371, 29720203, 29358611, 29100083, 31139143, 25726841, 23708187, 28191890, 31087664, 30728247, 28351718, 25730860, 28714951) -

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8

Pathogenic:1

Apr 10, 2024

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 glutamine, which is neutral and polar, at codon 323 of the GABRG2 protein (p.Arg323Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABRG2-related conditions (PMID: 23708187, 27864268, 29100083, 29358611). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60708). 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 GABRG2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 27864268). For these reasons, this variant has been classified as Pathogenic. -

Generalized epilepsy with febrile seizures plus 3

Pathogenic:1

Jul 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

CAADphred>15 -

Inborn genetic diseases

Pathogenic:1

Oct 12, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R323Q pathogenic mutation (also known as c.968G>A), located in coding exon 8 of the GABRG2 gene, results from a G to A substitution at nucleotide position 968. The arginine at codon 323 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been determined to be the result of a de novo mutation in two patients with epileptic encephalopathies (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30; Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Electrophysiology functional studies indicate this variant results in altered GABAA-R chloride channel kinetics (Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

.;.;.;.;.;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.1

.;.;.;.;M;.;M;.;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

.;.;.;.;.;.;.;.;.;.;.;D;N;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;D;T;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;D;.;.

Polyphen

1.0, 1.0

.;.;.;.;D;.;D;.;.;.;.;.;.;.

Vest4

0.84

MutPred

0.85

.;.;.;.;Gain of ubiquitination at K324 (P = 0.0418);.;Gain of ubiquitination at K324 (P = 0.0418);.;Gain of ubiquitination at K324 (P = 0.0418);.;Gain of ubiquitination at K324 (P = 0.0418);.;.;Gain of ubiquitination at K324 (P = 0.0418);

MVP

0.89

MPC

2.7

ClinPred

1.0

GERP RS

5.9

Varity_R

0.93

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over