Submissions for variant NM_001127644.2(GABRA1):c.884C>T (p.Thr295Ile)

dbSNP: rs796052496

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187504	SCV000241098	likely pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing	The Thr295Ile missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Thr295Ile in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Isoleucine residue. Thr295Ile alters a highly conserved position in the second transmembrane domain of the GABRA1 protein and another missense variant at a nearby codon (Thr294Ile) has been reported as a de novo variant in an individual with epilepsy. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, the Thr295Ile variant is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253629	SCV001429456	likely pathogenic	Developmental and epileptic encephalopathy, 19	2018-08-20	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Invitae	RCV001857613	SCV002216801	uncertain significance	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the GABRA1 protein (p.Thr295Ile). 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 expected to disrupt GABRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 205525). This missense change has been observed in individual(s) with GABRA1-related conditions (PMID: 29655203). This variant is not present in population databases (gnomAD no frequency).