Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494267 | SCV000582204 | likely pathogenic | not provided | 2015-09-24 | criteria provided, single submitter | clinical testing | The T185I variant in the GABRB3 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The T185I 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 T185I variant 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (E180G) has been reported in the Human Gene Mutation Database in association with a GABRB3-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T185I variant is a strong candidate for a disease-causing variant,however the possibility it may be a rare benign variant cannot be excluded |
| Labcorp Genetics |
RCV003766773 | SCV004573336 | pathogenic | Epilepsy, childhood absence, susceptibility to, 1; Epilepsy, childhood absence, susceptibility to, 5 | 2023-07-13 | 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 185 of the GABRB3 protein (p.Thr185Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 28053010, 34698933). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 429597). 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 GABRB3 protein function. For these reasons, this variant has been classified as Pathogenic. |