Submissions for variant NM_012084.4(GLUD2):c.1492T>G (p.Ser498Ala)

gnomAD frequency: 0.03160  dbSNP: rs9697983

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251924	SCV002523836	uncertain significance	See cases	2020-11-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4
Neuberg Centre For Genomic Medicine, NCGM	RCV000022827	SCV004048538	uncertain significance	Parkinson disease, late-onset		criteria provided, single submitter	clinical testing	The GLUD2 c.1492T>G variant has been reported previously to be a modifier of age of onset in Parkinsonism patient (Plaitakis A et al). The variant has been submitted to ClinVar as Pathogenic based on the same publication. Experimental studies have shown that estrogen hormones inhibited the enhanced basal activity of the X-linked variant much more powerfully than that of the widely expressed hGDH1. Hence, it seems likely that, in females, estrogens may nullify the gain-of-function effects observed in male patients by blocking the overactive variant enzyme from metabolizing increased amounts of glutamate (and, in the process, damaging nigral cells). Understanding the mechanisms by which the variant hastens the commencement of PD symptoms could provide a means for retarding the development of this disorder (Plaitakis A et al). This variant is reported in gnomAD database at a frequency of 2.756% with 2188 number of hemizygotes. The allele frequency is however expected to be skewed in gnomAD. The amino acid Ser at position 498 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser498Ala in GLUD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Considering the relative high frequency of the variant in the gnomAD, this variant has been classified as Uncertain significance.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000022827	SCV005373939	benign	Parkinson disease, late-onset	2024-09-22	criteria provided, single submitter	clinical testing
OMIM	RCV000022827	SCV000044116	benign	Parkinson disease, late-onset	2010-03-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003974852	SCV004787764	benign	GLUD2-related disorder	2022-04-06	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).