Submissions for variant NM_000170.3(GLDC):c.1545G>C (p.Arg515Ser)

dbSNP: rs121964976

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000449527	SCV000537854	pathogenic	Obesity; Global developmental delay; Generalized epilepsy	2016-11-28	criteria provided, single submitter	clinical testing	The c.1545G>C (p.Arg515Ser) missense variant in the GLDC gene is previously reported in the literature and is a recognized cause of nonketotic hyperglycinemia. Homozygous and compound heterozygous loss-of-function pathogenic variants in this gene are associated with nonketotic hyperglycinemia, also known as glycine encephalopathy. This variant has been observed at a high frequency among individuals with nonketotic hyperglycinemia and has been seen in both the homozygous and compound heterozygous state with other known pathogenic variants, including large exonic deletions. Functional studies have shown that the presence of this variant causes the protein to be unstable with no residual functional activity. This variant has not been observed in either 1000 Genomes or NHLBI Exome Sequencing Project datasets, but has been observed in ExAC at an allele frequency of 0.00015, with no homozygotes reported. This variant involves a weakly conserved nucleotide but highly conserved amino acid. PolyPhen-2, SIFT, and MutationTaster all predict this variant to be damaging. Therefore, based on the reports and functional evidence in the literature, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012765	SCV000636358	pathogenic	Glycine encephalopathy	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 515 of the GLDC protein (p.Arg515Ser). This variant is present in population databases (rs121964976, gnomAD 0.02%). This missense change has been observed in individual(s) with glycine encephalopathy (nonketotic hyperglycininemia) (PMID: 10873393, 11286506, 12126939, 17361008, 26179960; internal data). 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: 11985). 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%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV004566732	SCV000894478	pathogenic	Glycine encephalopathy 1	2024-03-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000012765	SCV000916266	pathogenic	Glycine encephalopathy	2018-10-31	criteria provided, single submitter	clinical testing	The GLDC c.1545G>C (p.Arg515Ser) variant has been reported in five studied and was found in a total of 60 probands including four in a homozygous state, 48 in a compound heterozygous state, and 11 in a heterozygous state with an undetected second allele (Toone et al. 2000; Toone et al. 2001, Sellner et al. 2005; Kanno et al. 2007; Coughlin et al. 2016). A large deletion may not have been identified in the heterozygous probands with the testing methods used (Toone et al. 2001, Sellner et al. 2005). The p.Arg515Ser variant is identified as a founder variant in the United Kingdom (Coughlin et al. 2016). Control data are unavailable for the p.Arg515Ser variant, which is reported at a frequency of 0.000189 in the European (non-Finnish) population of the Genome Aggregation Database. The crystal structure of the p.Arg515Ser variant predicts the variant protein to be destabilized (Nakai et al. 2005). Based on the evidence, the p.Arg515Ser variant is classified as pathogenic for glycine encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012765	SCV000919471	pathogenic	Glycine encephalopathy	2018-06-29	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.1545G>C (p.Arg515Ser) 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 9e-05 in 277284 control chromosomes (gnomAD and publication). The variant, c.1545G>C, has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia)(Sellner_2005, Toone_2001). It has also been reported as a commonly observed missesne variant present in six percent of all GLDC alleles (PMID: 27362913, Coughlin et al, 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. The most pronounced variant effect results in <10% of normal activity. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001582476	SCV001812841	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with significant impairment of enzyme function (Swanson et al., 2015); In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 10873393, 11286506, 15272469, 33524012, 26179960, 12126939, 15670722, 28794088, 20301531, 17361008, 32421718, 27362913)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000012765	SCV001870362	pathogenic	Glycine encephalopathy	2021-04-26	criteria provided, single submitter	research	ACMG codes:PS3, PS4, PM2, PM3, PP3, PP5
Revvity Omics, Revvity	RCV000012765	SCV002024839	pathogenic	Glycine encephalopathy	2019-01-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012765	SCV004041465	pathogenic	Glycine encephalopathy	2023-08-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000012765	SCV004046062	pathogenic	Glycine encephalopathy		criteria provided, single submitter	clinical testing	This established pathogenic variant has been reported in individuals with glycine encephalopathy (nonketotic hyperglycinemia) (PMID: 17361008, 26179960, 11286506), and identified as a founder variant in the United Kingdom (PMID: 20301531, 27362913). Functional studies have shown that this variant leads to a protein with no measurable residual functional activity (PMID: 26179960). The c.1545G>C (p.Arg515Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0088% (25/282836) and is absent in the homozygous state. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1545G>C (p.Arg515Ser) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398490	SCV004111728	pathogenic	GLDC-related disorder	2023-03-31	criteria provided, single submitter	clinical testing	The GLDC c.1545G>C variant is predicted to result in the amino acid substitution p.Arg515Ser. This variant is one of the most common pathogenic variants for non-ketotic hyperglycinaemia, also known as glycine encephalopathy (Toone et al. 2000. PubMed ID: 10873393; Coughlin et al. 2017. PubMed ID: 27362913; Van Hove et al. 2019. PubMed ID: 20301531). Experimental studies indicate the p.Arg515Ser substitution impairs enzyme stability and function (Toone et al. 2000. PubMed ID: 10873393; Swanson et al. 2015. PubMed ID: 26179960). It is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-6589230-C-G). This variant is interpreted as pathogenic.
OMIM	RCV004566732	SCV000033000	pathogenic	Glycine encephalopathy 1	2001-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000012765	SCV000086734	not provided	Glycine encephalopathy		no assertion provided	literature only
Counsyl	RCV000012765	SCV000789135	likely pathogenic	Glycine encephalopathy	2017-01-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000012765	SCV001457129	pathogenic	Glycine encephalopathy	2020-09-16	no assertion criteria provided	clinical testing