Submissions for variant NM_000170.3(GLDC):c.2852C>A (p.Ser951Tyr)

gnomAD frequency: 0.00036  dbSNP: rs147472391

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669842	SCV000794634	uncertain significance	Non-ketotic hyperglycinemia	2017-10-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000669842	SCV000897524	uncertain significance	Non-ketotic hyperglycinemia	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669842	SCV000931199	likely pathogenic	Non-ketotic hyperglycinemia	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 951 of the GLDC protein (p.Ser951Tyr). This variant is present in population databases (rs147472391, gnomAD 0.07%). This missense change has been observed in individual(s) with glycine encephalopathy and/or nonketotic hyperglycinemia (PMID: 27362913). 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: 554247). 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 not expected to disrupt GLDC protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLDC function (PMID: 16802295). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics	RCV000992083	SCV001144068	uncertain significance	not provided	2019-06-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000669842	SCV001330583	uncertain significance	Non-ketotic hyperglycinemia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000992083	SCV002000729	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically mice with the variant, showing an accumulation of glycine in the liver and brain (PMID: 32743799); 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: 27362913, 16802295, 29988937, 29205322, 32743799)
Revvity Omics, Revvity	RCV000669842	SCV002018463	likely pathogenic	Non-ketotic hyperglycinemia	2021-08-06	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000669842	SCV002099377	uncertain significance	Non-ketotic hyperglycinemia	2021-02-26	criteria provided, single submitter	clinical testing	The c.2852C>A (p.Ser951Tyr) variant identified in the GLDC gene substitutes a moderately conserved Serine for Tyrosine at amino acid 951/1021 (exon 24/25). This variant is found with low frequency in gnomAD(v3.1) (55 heterozygotes, 0 homozygotes, allele frequency: 3.6e-4) suggesting it is not a common benign variant in the populations represented in that databases. In silico algorithms predict this variant to be Damaging (SIFT; score: 0.00) and Pathogenic (REVEL; score: 0.6449) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:554247), and has been reported in 2 individuals with Glycine Encephalopathy [PMID:16802295; PMID:27362913], and has also been observed in a fetus with anencephaly [PMID:29205322], although its clinical relevance to the anencephaly phenotype is unclear. Expression analysis in COS-7 cells from an individual with the p.Ser951Tyr variant suggest this variant has approximately 39% residual enzyme activity [PMID:16802295], and this finding is supported by recent studies in an equivalent mouse model (GldcS956Ymice) [PMID:32743799]. The c.2852C>A (p.Ser951Tyr) variant identified in the GLDC gene is reported as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271558	SCV002556205	uncertain significance	not specified	2022-06-28	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.2852C>A (p.Ser951Tyr) 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 0.00034 in 251124 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.00034 vs 0.0031), allowing no conclusion about variant significance. c.2852C>A has been reported in the literature in individuals affected with Non-Ketotic Hyperglycinemia (del Toro_2006, Coughlin_2017) and in one individual with anencephaly (Ishida_2018). These data indicate that the variant may be associated with disease. An assay using transiently transfected COS7 cells showed that the variant had 39% enzymatic activity compared to wild type (del Toro_2006). Additionally, a mouse model found that animals carrying the corresponding variant in mouse Gldc in compound heterozygosity with a null allele had glycine accumulation at 1.3-fold what is seen in control animals (Leung_2020). Nine ClinVar submitters have assessed the variant since 2014: seven classified the variant as VUS, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002531239	SCV003691390	uncertain significance	Inborn genetic diseases	2021-09-13	criteria provided, single submitter	clinical testing	The c.2852C>A (p.S951Y) alteration is located in exon 24 (coding exon 24) of the GLDC gene. This alteration results from a C to A substitution at nucleotide position 2852, causing the serine (S) at amino acid position 951 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000669842	SCV004167593	likely pathogenic	Non-ketotic hyperglycinemia	2023-02-28	criteria provided, single submitter	clinical testing	GLDC NM_000170.2 p.Ser951Tyr (c.2852C>A): This variant has been reported in the literature in trans with a pathogenic variant in 1 individual with nonketotic hyperglycinemia (NKH), in the heterozygous state in 1 individual with features suggestive of NKH, and in trans with a pathogenic variant in multiple individuals with NKH at a commercial laboratory (del Toro 2006 PMID: 16802295; Coughlin 2017 PMID: 27362913; GeneDx, personal communication). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.08% [12/15282]; https://gnomad.broadinstitute.org/variant/9-6534775-G-T?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar, with classifications ranging from VUS to pathogenic (Variation ID: 554247). Evolutionary conservation and computational predictive tools for this variant weakly suggest that it might impact protein structure or function. An in vitro functional study found that cells with this variant had approximately 39% residual enzymatic activity compared to the wild-type (del Toro 2006 PMID: 16802295). Mouse models have supported this, showing that this variant results in mild but still significant elevation of plasma glycine compared to the wild-type, as well as increased glycine accumulation in the brain (Leung 2020 PMID: 32743799). However, these studies may not accurately represent biological function in humans. Based on the above data, this variant is classified as likely pathogenic but may also be considered hypomorphic, likely causing disease when in trans with a more deleterious pathogenic variant.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003889956	SCV004704617	likely pathogenic	Glycine encephalopathy 1	2024-02-21	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in trans (on opposite alleles) with a pathogenic variant in one individual with nonketotic hyperglycinemia (NKH), in the heterozygous state in one individual with features suggestive of NKH, and in trans with a pathogenic variant in an individual with NKH at a commercial laboratory (del Toro 2006 PMID: 16802295; Coughlin 2017 PMID: 27362913; ClinVar Variation ID: 554247). It is present in gnomAD (Highest reported MAF, non-bottlenecked: 0.05% [570/1165280]; https://gnomad.broadinstitute.org/variant/9-6534775-G-T?dataset=gnomad_r4); please note, disease-causing variants may be present in control databases at low frequencies, reflective of carrier status, incomplete penetrance, and/or variable expressivity. An in vitro functional study found that this variant confers approximately 39% residual enzyme activity compared to the wild type (del Toro 2006 PMID: 16802295). Mouse models have supported this, showing that this variant results in mild but still significant elevation of plasma glycine compared to the wild type, as well as increased glycine accumulation in the brain (Leung 2020 PMID: 32743799). Evolutionary conservation and computational predictive tools for this variant weakly support a potential deleterious effect on protein structure or function. The experimental data available for this variant and other variants with similar effects on enzyme activity are consistent with this variant resulting in an attenuated NKH phenotype when homozygous or compound heterozygous with another variant with residual enzyme activity (Coughlin 2017 PMID: 27362913). In summary, this variant is classified as likely pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003889956	SCV005051797	likely pathogenic	Glycine encephalopathy 1	2024-02-01	criteria provided, single submitter	curation
Natera, Inc.	RCV000669842	SCV002075710	uncertain significance	Non-ketotic hyperglycinemia	2020-01-18	no assertion criteria provided	clinical testing