Submissions for variant NM_001127644.2(GABRA1):c.641G>A (p.Arg214His)

dbSNP: rs886039373

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254956	SCV000321688	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Published functional study demonstrates a damaging effect due to impaired GABA-A receptor inhibitory function (Johannesen et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27353043, 30185235, 32238909, 27535533, 27521439)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000417089	SCV000494656	likely pathogenic	Developmental and epileptic encephalopathy, 19	2016-07-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525742	SCV000647922	pathogenic	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the GABRA1 protein (p.Arg214His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome-like phenotype (PMID: 27353043). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265162). 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 GABRA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GABRA1 function (PMID: 27353043). For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000417089	SCV001160787	likely pathogenic	Developmental and epileptic encephalopathy, 19	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS2, PM2, PP2, PP3, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000254956	SCV001247875	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GABRA1: PM2, PM5, PM6, PS4:Moderate, PP2, PP3, PS3:Supporting
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000417089	SCV003924016	pathogenic	Developmental and epileptic encephalopathy, 19	2023-05-10	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796136	SCV005416085	pathogenic	Epilepsy, idiopathic generalized, susceptibility to, 13; Developmental and epileptic encephalopathy, 19		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PS4_Moderate+PM6_Strong+PM1
Genatak	RCV000417089	SCV001193765	pathogenic	Developmental and epileptic encephalopathy, 19	2018-06-23	no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000417089	SCV002570057	pathogenic	Developmental and epileptic encephalopathy, 19	2002-09-08	no assertion criteria provided	research