rs587777308
Positions:
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
NM_001127644.2 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 6.71
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]
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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 gene, where missense usually causes diseases (based on misZ statistic), GABRA1. . Gene score misZ 3.1498 (greater than the threshold 3.09). Trascript score misZ 4.2662 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GABRA1 | NM_001127644.2 | c.335G>A | p.Arg112Gln | missense_variant | 5/10 | ENST00000393943.10 | NP_001121116.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GABRA1 | ENST00000393943.10 | c.335G>A | p.Arg112Gln | missense_variant | 5/10 | 1 | NM_001127644.2 | ENSP00000377517.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Apr 16, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | GABRA1: PM6:Strong, PM1, PM2, PS4:Moderate, PP2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2024 | 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) - |
Developmental and epileptic encephalopathy, 19 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 08, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2016 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Dec 08, 2017 | - - |
Epilepsy Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PS2,PP4,PM2,PP3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;D;T;D;.;D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;.;.;.;D;.;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;L;L;L;.;L;.;L;.;L
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N;N;N;N;.;.;.;.;.
REVEL
Pathogenic
Sift
Benign
.;T;T;T;T;D;.;.;.;.;.
Sift4G
Benign
.;T;T;T;T;T;.;.;.;T;.
Polyphen
P;P;P;P;P;.;P;.;P;.;P
Vest4
0.82, 0.64, 0.82, 0.82
MutPred
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
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at