Submissions for variant NM_000170.3(GLDC):c.806C>T (p.Thr269Met)

gnomAD frequency: 0.00001  dbSNP: rs386833587

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049513	SCV000793463	likely pathogenic	Glycine encephalopathy	2017-08-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049513	SCV000919469	pathogenic	Glycine encephalopathy	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.806C>T (p.Thr269Met) results in a non-conservative amino acid change in 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 1.6e-05 in 246244 control chromosomes. c.806C>T has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) both as a compound heterozygous and homozygous allele (Conter_2006, Coughlin_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 residual enzyme activity, where <10% of normal activity was observed in vitro (Swanson_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049513	SCV000945814	pathogenic	Glycine encephalopathy	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 269 of the GLDC protein (p.Thr269Met). This variant is present in population databases (rs386833587, gnomAD 0.006%). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 16450403, 16601880, 27362913). ClinVar contains an entry for this variant (Variation ID: 56104). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLDC protein function. Experimental studies have shown that this missense change affects GLDC function (PMID: 26179960). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001528427	SCV002552706	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant leads to an unstable protein and reduced enzyme activity (Swanson et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15272469, 26179960, 16601880, 16450403, 27362913)
Fulgent Genetics, Fulgent Genetics	RCV005003444	SCV002790901	pathogenic	Glycine encephalopathy 1	2023-12-20	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000049513	SCV004175266	pathogenic	Glycine encephalopathy	2023-07-07	criteria provided, single submitter	clinical testing	The GLDC c.806C>T variant is classified as PATHOGENIC (PS3, PS4, PP3) The GLDC c.806C>T variant is a single nucleotide change in exon 6/25 of the GLDC gene, which is predicted to change the amino acid threonine at position 269 in the protein to methionine. This variant has been reported in both homozygous and compound heterozygous state in multiple individuals with Glycine encephalopathy (PMID:16450403, PMID:16601880, PMID:27362913) (PS4). Functional studies show <10% of normal enzyme activity compared to wildtype (PMID:26179960) (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs386833587) and in the HGMD database: CM042354. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 56104).
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049513	SCV000081949	probable-pathogenic	Glycine encephalopathy		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049513	SCV001458165	pathogenic	Glycine encephalopathy	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528427	SCV001740165	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001528427	SCV001808525	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528427	SCV001928013	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000049513	SCV004804595	not provided	Glycine encephalopathy		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 07-23-2022 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.