Submissions for variant NM_000170.3(GLDC):c.2714T>G (p.Val905Gly)

gnomAD frequency: 0.00003  dbSNP: rs188269735

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792883	SCV000932209	pathogenic	Glycine encephalopathy	2024-04-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 905 of the GLDC protein (p.Val905Gly). This variant is present in population databases (rs188269735, gnomAD 0.04%). This missense change has been observed in individual(s) with non-ketotic hypoglycemia (PMID: 16450403, 26179960, 28244183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 639955). 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%. Experimental studies have shown that this missense change affects GLDC function (PMID: 28244183). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001092997	SCV001249761	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000792883	SCV002018468	likely pathogenic	Glycine encephalopathy	2020-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000792883	SCV002765945	pathogenic	Glycine encephalopathy	2022-11-10	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.2714T>G (p.Val905Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250296 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (4.8e-05 vs 0.0031), allowing no conclusion about variant significance. c.2714T>G has been reported in the literature as a biallelic (homozygous or compound heterozygous) genotype in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Coughlin_2017, Bravo-Alonso_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Bravo-Alonso_2017). The most pronounced variant effect results in 1-10% of normal P-protein exchange activity in-vitro. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005004424	SCV002787944	likely pathogenic	Glycine encephalopathy 1	2024-05-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000792883	SCV001457113	pathogenic	Glycine encephalopathy	2020-09-16	no assertion criteria provided	clinical testing