rs587777308

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_001127644.2(GABRA1):c.335G>A(p.Arg112Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA1
NM_001127644.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:1

Conservation

PhyloP100: 6.71

Variant links:

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GABRA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.1498 (above the threshold of 3.09). Trascript score misZ: 4.2662 (above the threshold of 3.09). GenCC associations: The gene is linked to juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant 5-161873196-G-A is Pathogenic according to our data. Variant chr5-161873196-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-161873196-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 5 of 10	ENST00000393943.10	NP_001121116.1	P14867

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 5 of 10	1	NM_001127644.2	ENSP00000377517.4		P14867

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple patients with epilepsy previously tested at GeneDx and in the published literature, including as a de novo variant with or without confirmed parentage (PMID: 24623842, 26918889, 27521439, 31056671, 29056246); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24623842, 26918889, 26073591, 31440721, 31056671, 27521439, 29056246) -

Apr 16, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRA1: PM6:Strong, PM1, PM2, PS4:Moderate, PP2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 19

Pathogenic:3

Apr 08, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.84 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000127074 /PMID: 24623842).A different missense change at the same codon (p.Arg112Trp) has been reported to be associated with GABRA1 related disorder (ClinVar ID: VCV000947414). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Oct 11, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R112Q pathogenic mutation (also known as c.335G>A), located in coding exon 4 of the GABRA1 gene, results from a G to A substitution at nucleotide position 335. The arginine at codon 112 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 one individual with epileptic encephalopathy in our laboratory. In addition, this variant has been reported in two individuals in the literature with epileptic encephalopathy, one of which was reportedly de novo (Carvill GL et al. Neurology, 2014 Apr;82:1245-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13

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 112 of the GABRA1 protein (p.Arg112Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a variety of seizure phenotypes including early infantile epilepsy and Dravet syndrome (PMID: 24623842, 26918889, 27521439). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127074). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GABRA1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 19;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13

Pathogenic:1

Dec 08, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS2,PP4,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.81

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

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

1.4

L;L;L;L;L;.;L;.;L;.;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.7

.;N;N;N;N;N;.;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Benign

0.093

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

Sift4G

Benign

0.59

.;T;T;T;T;T;.;.;.;T;.

Polyphen

0.83

P;P;P;P;P;.;P;.;P;.;P

Vest4

0.82, 0.64, 0.82, 0.82

MutPred

0.51

Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);.;Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);Loss of MoRF binding (P = 0.0142);

MVP

0.92

MPC

1.4

ClinPred

0.86

GERP RS

5.8

Varity_R

0.37

gMVP

0.90

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

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