Submissions for variant NM_001127644.2(GABRA1):c.640C>T (p.Arg214Cys)

dbSNP: rs727503940

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255903	SCV000321687	pathogenic	not provided	2015-03-10	criteria provided, single submitter	clinical testing	The R214C missense change in the GABRA1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R214C missense change is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and a missense variant in a nearby residue (D219N) has been reported in association with idiopathic generalized epilepsy (Lachance-Touchette et al., 2011). In silico analysis predicts R214C is probably damaging to the protein structure/function. Additionally, R214C has been previously seen at GeneDx as a de novo mutation in another patient referred for epilepsy testing. Therefore, R214C is considered to be a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817598	SCV000958167	pathogenic	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the GABRA1 protein (p.Arg214Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy and/or neurodevelopmental disorders (PMID: 29655203; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265161). 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. This variant disrupts the p.Arg214 amino acid residue in GABRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27353043, 27521439). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500957	SCV002808168	likely pathogenic	Epilepsy, idiopathic generalized, susceptibility to, 13; Developmental and epileptic encephalopathy, 19	2022-02-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003137868	SCV003822718	pathogenic	Developmental and epileptic encephalopathy, 19	2022-03-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003137868	SCV004100770	likely pathogenic	Developmental and epileptic encephalopathy, 19	2023-10-24	criteria provided, single submitter	clinical testing	Criteria applied: PS2_MOD,PS4_MOD,PM1_SUP,PM2_SUP,PP2,PP3
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678794	SCV000804975	uncertain significance	Intractable seizure	2017-02-10	no assertion criteria provided	clinical testing