Submissions for variant NM_000170.3(GLDC):c.2963G>A (p.Arg988Gln)

gnomAD frequency: 0.00001  dbSNP: rs749512886

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669902	SCV000794702	uncertain significance	Glycine encephalopathy	2017-10-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669902	SCV001590583	pathogenic	Glycine encephalopathy	2024-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 988 of the GLDC protein (p.Arg988Gln). This variant is present in population databases (rs749512886, gnomAD 0.003%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 27362913, 28416785). ClinVar contains an entry for this variant (Variation ID: 554292). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 95%. This variant disrupts the p.Arg988 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27362913). 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004568533	SCV005051800	likely pathogenic	Glycine encephalopathy 1	2024-02-01	criteria provided, single submitter	curation
Neuberg Centre For Genomic Medicine, NCGM	RCV004568533	SCV005442686	likely pathogenic	Glycine encephalopathy 1	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense c.2963G>A p.Arg988Gln variant in gene has been previously reported in homozygous state in multiple individuals affected with Glycine encephalopathy Kose E et al. 2017; Farris J et al. 2020. The p.Arg988Gln variant has allele frequency 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain significance / Pathogenic. Multiple lines of computational evidence Polyphen - Probably damaging, SIFT – Damaging and Mutation Taster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change on GLDC gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 988 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic.