5-161873196-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3PP5
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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001127644.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRA1 | NM_001127644.2 | c.335G>A | p.Arg112Gln | missense_variant | 5/10 | ENST00000393943.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRA1 | ENST00000393943.10 | c.335G>A | p.Arg112Gln | missense_variant | 5/10 | 1 | NM_001127644.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2022 | Previously reported as a likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (Butler et al., 2017); 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, 29056246, 31056671, 27521439) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | GABRA1: PM6:Strong, PM1, PM2, PS4:Moderate, PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 16, 2014 | - - |
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 | Invitae | 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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at