ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.641G>A (p.Arg214His) (rs886039373)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254956 SCV000321688 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing The R214H variant in the GABRA1 gene has been observed as a de novo change in multiple unrelated individuals with epileptic encephalopathy referred for genetic testing at GeneDx and in the published literature (Johannesen et al., 2016; Fokstuen et al., 2016). Functional study showed R214H resulted in a significant loss-of-function in Xenopus laevisoocytes and impaired the function of the available WT subunit (Johannesen et al., 2016). The R214H variant is not observed in large population cohorts (Lek et al., 2016). The R214H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R214H as a pathogenic variant.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000417089 SCV000494656 likely pathogenic Epileptic encephalopathy, early infantile, 19 2016-07-05 criteria provided, single submitter clinical testing
Invitae RCV000525742 SCV000647922 pathogenic Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 214 of the GABRA1 protein (p.Arg214His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in two individuals affected with epileptic encephalopathy and one individual affected with a Dravet syndrome-like phenotype (PMID: 27353043). ClinVar contains an entry for this variant (Variation ID: 265162). Experimental studies have shown that this missense change reduces the conductance of the GABRA1-encoded ion channel (PMID: 27353043). For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000417089 SCV001160787 likely pathogenic Epileptic encephalopathy, early infantile, 19 2019-12-11 criteria provided, single submitter research ACMG evidence PS2, PM2, PP2, PP3, PP5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254956 SCV001247875 pathogenic not provided 2017-12-01 criteria provided, single submitter clinical testing
Genatak RCV000417089 SCV001193765 pathogenic Epileptic encephalopathy, early infantile, 19 2018-06-23 no assertion criteria provided clinical testing

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