Submissions for variant NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)

dbSNP: rs121909731

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185923	SCV000238878	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies demonstrate reduced sensitivity to GTP inhibition (Barrosse-Antle et al., 2017); This variant is associated with the following publications: (PMID: 26759084, 28165182, 25008049, 9571255, 28135719, 31119523, 27188453, 10636977, 30306091, 30098243, 23869231, 26758964, 31785789)
Invitae	RCV000017502	SCV000938633	pathogenic	Hyperinsulinism-hyperammonemia syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 498 of the GLUD1 protein (p.Ser498Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUD1-related conditions (PMID: 9571255, 23869231, 25008049, 26759084, 27188453, 28165182). In at least one individual the variant was observed to be de novo. This variant is also known as c.1506C>T (p.Ser445Leu). ClinVar contains an entry for this variant (Variation ID: 16122). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000017502	SCV002820181	pathogenic	Hyperinsulinism-hyperammonemia syndrome		criteria provided, single submitter	clinical testing	The missense variant c.1493C>T(p.Ser498Leu) in GLUD1 gene has been reported in the literature in individuals with GLUD1-related conditions and has been observed to be de novo in multiple individuals affected with GLUD1-related conditions (Sarajlija A et.al.,2016). This variant has been reported to the ClinVar database as Pathogenic. The p.Ser498Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ser at position 498 is changed to a Leu 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.Ser498Leu in GLUD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Illumina Laboratory Services, Illumina	RCV000017502	SCV004101316	pathogenic	Hyperinsulinism-hyperammonemia syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The GLUD1 c.1493C>T (p.Ser498Leu) missense variant, which is also known as p.Ser445Leu, is located in the allosteric domain of glutamate dehydrogenase 1. Across a selection of the peer-reviewed literature, the variant has been reported in at least six unrelated individuals with hyperinsulinism-hyperammonemia syndrome, including in a de novo state (PMID: 9571255; 19046187; 19344873; 26759084; 28165182). Lymphoblasts from patients showed impaired inhibition of glutamate dehydrogenase by GTP. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the p.Ser498Leu variant may impact the gene or gene product, and functional studies in HEK293T cells have shown that this variant leads to a gain in enzyme function by reducing the sensitivity of glutamate dehydrogenase to inhibition by GTP (PMID: 28165182). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1493C>T (p.Ser498Leu) variant is classified as pathogenic for hyperinsulinism-hyperammonemia syndrome.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000017502	SCV004806805	uncertain significance	Hyperinsulinism-hyperammonemia syndrome	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000017502	SCV000037774	pathogenic	Hyperinsulinism-hyperammonemia syndrome	2000-01-01	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000017502	SCV002070460	pathogenic	Hyperinsulinism-hyperammonemia syndrome	2019-04-03	no assertion criteria provided	clinical testing	DNA sequence analysis of the GLUD1 gene demonstrated a sequence change, c.1493C>T, in exon 11 that results in an amino acid change, p.Ser498Leu. This sequence change is absent from population databases such as ExAC and gnomAD, and it affects a moderately conserved amino acid residue located in a domain of the GLUD1 protein that is known to be functional. This sequence change has previously been identified in patients with hyperinsulinism-hyperammonemia syndrome (named as p.Ser445Leu) in the de-novo state (Stanley et al,1998). In the affected patients, glutamate dehydrogenase had reduced sensitivity to inhibition by GTP (Stanley et al,1998).