ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

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.

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; Invitae). 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). 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%. For these reasons, this variant has been classified as Pathogenic.

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.

ACMG codes:PS3, PS4, PM2, PM3, PP3, PP5