GLS was first reported in relation to autosomal dominant infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development due to GLS hyperactivity in 2019 (Rumping L, et al., 2019, PMID: 30239721). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two missense variants (Ser482Cys and His461Leu) have been reported from two probands in two publications (PMIDs: 30239721, 37151363). To validate enhanced catalytic activity of the Ser482Cys GLS variant, a HEK293 cell model with inducible expression of Ser482Cys-GLS was generated. Induction of Ser482Cys-GLS again strongly increased the glutamate/glutamine ratio (as in the patient) while induction of wild-type GLS had no effect (PMID: 30239721). Experimentally, this gene-disease relationship is supported by its role in the production of glutamate (PMID: 12963351), the resulting oxidative stress found in the patient as a consequence of glutamate excess, which contributes to the ophthalmologic phenotype (PMID: 30239721), and a zebrafish model with partial recapitulation of disease (PMID: 30239721). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This gene disease relationship was originally approved by the Aminoacidopathy GCEP on July 9, 2021. It was recurated on July 26, 2024 with new evidence (PMID: 37151363) resulting in no change of classificaiton.
Of note, two inborn errors of metabolism are caused by opposite defects in GLS. GLS deficiency due to loss‐of‐function [OMIM #618328/618412] in biallelic variants results in elevated glutamine plasma levels and a phenotypic spectrum of ataxia, optic atrophy, developmental delay, neonatal seizures, and neonatal death. The opposite biochemical defect has been described with GLS hyperactivity [OMIM #618339] caused by de novo heterozygous missense variants in GLS. Per ClinGen Lumping and Splitting criteria these were considered two seperate disease entities based on differences in moleclar mechanism, phenotype, and inheritance pattern. The autosomal recessive GLS deficiency was curated seperately.
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