Submissions for variant NM_001127644.2(GABRA1):c.335G>A (p.Arg112Gln)

dbSNP: rs587777308

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000153292	SCV000241089	pathogenic	not provided	2024-04-15	criteria provided, single submitter	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705072	SCV000834052	pathogenic	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2023-12-13	criteria provided, single submitter	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.
Ambry Genetics	RCV000623344	SCV000847991	pathogenic	Inborn genetic diseases	2016-10-11	criteria provided, single submitter	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.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000760281	SCV000890121	pathogenic	Epilepsy, idiopathic generalized, susceptibility to, 13; Developmental and epileptic encephalopathy, 19	2017-12-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000153292	SCV001247874	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	GABRA1: PM6:Strong, PM1, PM2, PS4:Moderate, PP2
OMIM	RCV000114937	SCV000148835	pathogenic	Developmental and epileptic encephalopathy, 19	2014-04-08	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000153292	SCV000202769	uncertain significance	not provided	2014-04-16	flagged submission	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000153292	SCV001809444	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000153292	SCV001951088	pathogenic	not provided		no assertion criteria provided	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000114937	SCV001984753	pathogenic	Developmental and epileptic encephalopathy, 19		no assertion criteria provided	clinical testing