GLDC

protein-coding

glycine decarboxylase

Gene summary

Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

MANE transcript

NM_000170.3

Inheritance

ClinVar variants

P:561U:695B:706

Top phenotype

Glycine encephalopathy 1

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr9:6,532,467-6,645,729

External References & Databases

Ensembl (ENSG00000178445)

Transcript & Mutation Effects

hg38 • Region Span ~113.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017354

Submitter: Orphanet

glycine encephalopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958179

Submitter: PanelApp Australia

atypical glycine encephalopathySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0015010

Submitter: Orphanet

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Natera

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Myriad Women's Health

glycine encephalopathy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0958179

Submitter: G2P

glycine encephalopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Labcorp Genetics (formerly Invitae)

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: ClinGen

The relationship between GLDC and glycine encephalopathy (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of October 19th, 2018. Variants in GLDC, which encodes the P-protein (glycine decarboxylase) of the glycine cleavage system, were first reported in humans with this disease as early as 1991 (Kure et al, PMID 1996985). At least 300 unique variants (52% missense mutations, 11% nonsense mutations, 10% splice-site mutations, 6% small insertions/deletions, and 21% exonic CNVs) have been reported in humans (Coughlin et al, 2017, PMID 27362913; van Hove et al, 2013, PMID 20301531). Variants in this gene have been reported in about 80% of probands with glycine encephalopathy (nonketotic hyperglycinemia, NKH); most of the remaining patients have variants in AMT which encodes the T-protein of the glycine cleavage system. Ten patients and 12 unique variants in GLDC are included here (Kure et al, 1991, PMID 1996985; Conter et al, 2006, PMID 16601880; Ezgu et al, 2014, PMID 24407464; Swanson et al, 2015, PMID 26179960; Coughlin et al, 2017, PMID 27362913). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, while most variants are private, a founder variant, p.Ser564Ile, accounts for about 70% of GLDC variants in the Finnish population (Kure et al, 1992, PMID 1634607), and other recurrent variants have been reported (Coughlin et al, 2017, PMID 27362913). The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the P protein (glycine carboxylase) in the glycine cleavage system, and a mouse model (Pai et al, 2015, PMID 25736695). In summary, GLDC is definitively associated with autosomal recessive glycine encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

neonatal glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017353

Submitter: Orphanet

Clinical Genomic Database (CGD)

Glycine encephalopathy 1AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Treatment may be less effective for individuals with severe disease; however, aggressive early treatment with sodium benzoate and N-methyl D-aspartate receptor site antagonists in individuals with variants associated with residual GCS enzyme activity have been reported to result in improved outcomes

Refs: 10873393; 12402263; 15077252; 15236413; 15851735; 16151895; 16404748; 16450403; 17361008; 20301531; 20933183; 21411353; 23349517

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLDC variants in ClinVar

17 Conditions Cataloged

Glycine encephalopathyTotal: 2283

not providedTotal: 451

Glycine encephalopathy 1Total: 283

not specifiedTotal: 151

Inborn genetic diseasesTotal: 108

GLDC-related disorderTotal: 64

GLDC-related disordersTotal: 23

Epileptic encephalopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000170.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	25 clinvar	657 clinvar	5 clinvar	689
missense	33 clinvar	158 clinvar	665 clinvar	39 clinvar	5 clinvar	900
nonsense	64 clinvar	62 clinvar	1 clinvar			127
start loss	2 clinvar					2
frameshift	95 clinvar	60 clinvar	1 clinvar			156
splice donor/acceptor (+/-2bp)	32 clinvar	53 clinvar	3 clinvar			88
Total	227	334	695	696	10	1962

Highest pathogenic variant AF is 0.0004436996

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000170.3	RefSeq	NP_000161.2	25	MANE Select
ENST00000321612.8	Ensembl	ENSP00000370737.4	25	MANE Select
ENST00000463305.1	Ensembl	ENSP00000491209.1	3	Standard
ENST00000638274.1	Ensembl	ENSP00000491487.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycine, serine and threonine metabolism - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia
Ammonia Recycling

Biological Process

glycine catabolic process
glycine decarboxylation via glycine cleavage system
electron transport chain
response to methylamine
response to lipoic acid

Molecular Function

glycine dehydrogenase (decarboxylating) activity
electron transfer activity
glycine binding
lyase activity
enzyme binding

Cellular Component

nucleus
mitochondrion
mitochondrial matrix
plasma membrane
glycine cleavage complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321612
Coding exons: 25
Length: 113187
Individuals with no LoFs: 125639
Homozygous LoFs: 0
Heterozygous LoFs: 109
Defined: 125748
p: 0.000434

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.59	645	541	1.19	0.0000303	6656
Missense (PolyPhen)		256	245.66	1.0421		2936
Synonymous	-4.81	292	205	1.43	0.0000124	1961
Loss of Function	0.913	46	53.2	0.865	0.00000292	645

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00059	0.00059	rare
South Asian	0.00043	0.00042	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The glycine cleavage system catalyzes the degradation of glycine. The P protein (GLDC) binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (GCSH). {ECO:0000269|PubMed:1993704, ECO:0000269|PubMed:1996985, ECO:0000269|PubMed:28244183}.;
Disease: DISEASE: Non-ketotic hyperglycinemia (NKH) [MIM:605899]: Autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms. {ECO:0000269|PubMed:11286506, ECO:0000269|PubMed:11592811, ECO:0000269|PubMed:1634607, ECO:0000269|PubMed:1996985, ECO:0000269|PubMed:28244183, ECO:0000269|PubMed:28737873}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.312

Intolerance Scores

LoFtool: 0.0943
RVIS EVS: -0.67
RVIS percentile EVS: 15.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.918

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium