Submissions for variant NM_001371727.1(GABRB2):c.911C>T (p.Ala304Val)

dbSNP: rs1580984866

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001534153	SCV001751054	pathogenic	not provided	2019-07-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29100083, 27171548, 30851244)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005094744	SCV005834988	pathogenic	Intellectual disability	2024-02-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 304 of the GABRB2 protein (p.Ala304Val). 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: 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1177964). 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 GABRB2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala304 amino acid residue in GABRB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33325057). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.