Submissions for variant NM_000170.3(GLDC):c.2182G>A (p.Gly728Arg)

dbSNP: rs386833542

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704610	SCV000833564	pathogenic	Glycine encephalopathy	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 728 of the GLDC protein (p.Gly728Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 27362913; Invitae). ClinVar contains an entry for this variant (Variation ID: 580932). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly728 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26179960, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000704610	SCV001363790	pathogenic	Glycine encephalopathy	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.2182G>A (p.Gly728Arg) results in a non-conservative amino acid change located in the Aromatic amino acid beta-eliminating lyase/threonine aldolase domain (IPR001597) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251430 control chromosomes. c.2182G>A (and a different variant with the same protein effect, c.2182G>C) have been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Coughlin_2017, Coughlin_2018 [erratum], Kure_2006, Ning_2021, Shellhaas_2017, Swanson_2022, Trujillano_2017). Further, a different missense variant at the same codon p.Gly728Glu has been classified as pathogenic in ClinVar (ID 2735246). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 29300369, 16450403, 34587689, 28733343, 35357708, 28116331). ClinVar contains an entry for this variant (Variation ID: 580932). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005046964	SCV005679313	likely pathogenic	Glycine encephalopathy 1	2024-05-16	criteria provided, single submitter	clinical testing