ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.335G>A (p.Arg112Gln) (rs587777308)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153292 SCV000202769 uncertain significance not provided 2014-04-16 criteria provided, single submitter clinical testing
GeneDx RCV000153292 SCV000241089 pathogenic not provided 2016-07-21 criteria provided, single submitter clinical testing The R112Q pathogenic variant in the GABRA1 gene has been reported previously in at least three individuals with infantile epilepsy and/or Dravet syndrome (Carvill et al., 2014; Kodera et al., 2016). This variant was not observed in approximately 6500 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 R112Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R112Q as a pathogenic variant
Ambry Genetics RCV000623344 SCV000740995 pathogenic Inborn genetic diseases 2015-07-29 criteria provided, single submitter clinical testing
Invitae RCV000705072 SCV000834052 pathogenic Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2020-01-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 112 of the GABRA1 protein (p.Arg112Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with a variety of seizure phenotypes including early infantile epilepsy and Dravet syndrome (PMID: 27521439, 26918889, 24623842). ClinVar contains an entry for this variant (Variation ID: 127074). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000717144 SCV000847991 pathogenic Seizures 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, juvenile myoclonic 5; Epileptic encephalopathy, early infantile, 19 2017-12-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000153292 SCV001247874 pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing
OMIM RCV000114937 SCV000148835 pathogenic Epileptic encephalopathy, early infantile, 19 2014-04-08 no assertion criteria provided literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000153292 SCV001809444 pathogenic not provided no assertion criteria provided clinical testing

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