Submissions for variant NM_000814.6(GABRB3):c.758C>T (p.Pro253Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486184	SCV000573312	likely pathogenic	not provided	2017-03-03	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the GABRB3 gene. The P253L variant has been reported previously as a de novo variant in the mosaic state in an individual with seizures, epileptic encephalopathy, severe intellectual disability and autistic features (Moller et al., 2017). The P253L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P253L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Additionally, missense variants in nearby residues (Q249K, L256Q) have been reported in the Human Gene Mutation Database in association with GABRB3-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004658	SCV001164106	likely pathogenic	Epileptic encephalopathy, early infantile, 43	2015-12-14	criteria provided, single submitter	clinical testing