Submissions for variant NM_001127644.2(GABRA1):c.1297A>G (p.Ile433Val)

gnomAD frequency: 0.00001  dbSNP: rs1057518405

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413392	SCV000492007	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing	The I433V variant in the GABRA1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I433V variant 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 I433V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I433V as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247171	SCV001420578	uncertain significance	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2023-06-18	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt GABRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 373415). This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 433 of the GABRA1 protein (p.Ile433Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000413392	SCV004241659	uncertain significance	not specified	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: GABRA1 c.1297A>G (p.Ile433Val) results in a conservative amino acid change located in the transmembrane domain of alpha subunits of type-A gamma-aminobutyric acid receptor (GABAAR) (IPR047024) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1297A>G in individuals affected with Developmental And Epileptic Encephalopathy, 19 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.