Glycine encephalopathy

Summary

Glycine encephalopathy (MONDO:0011612) is a disease (an umbrella term covering 6 Mondo subtypes) caused by variants in AMT and GLDC, with 6 cohort genes and 3 clinical trials. The dominant Reactome pathway is Glycine degradation (3 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: AMT (GenCC Definitive), GLDC (GenCC Definitive)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 3,221
• Phenotypes (HPO): 13
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.17	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.13	Portugal	Validated
Prevalence at birth	1-9 / 100 000	1.8	Finland	Validated
Prevalence at birth	1-9 / 100 000	1.59	Canada	Validated
Prevalence at birth	1-9 / 100 000	1	Saudi Arabia	Validated
Prevalence at birth	1-9 / 100 000	2	Portugal	Validated
Prevalence at birth	1-9 / 100 000	3.8	Israel	Validated
Prevalence at birth	1-9 / 100 000	8	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0002154	Hyperglycinemia	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0010851	EEG with burst suppression	Very frequent (80-99%)
HP:0012705	Abnormal metabolic brain imaging by MRS	Very frequent (80-99%)
HP:0100247	Recurrent singultus	Very frequent (80-99%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0005957	Breathing dysregulation	Frequent (30-79%)
HP:0005972	Respiratory acidosis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycine encephalopathy
Mondo ID	MONDO:0011612
OMIM	605899
Orphanet	407
DOID	DOID:9268
ICD-11	1491869639
NCIT	C84937
SNOMED CT	237939006
UMLS	C0751748
MedGen	155625
GARD	0007219
NORD	1512
Is cancer (heuristic)	no

Also known as: GCE · glycine encephalopathy · Glycine synthase deficiency · hyperglycinemia nonketotic · NKA · non-ketotic hyperglycinemia · Nonketotic Hyperglycinemia · nonketotic hyperglycinemia

Data availability: 3,221 ClinVar variants · 7 GenCC gene-disease records · 11 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › glycine encephalopathy

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Subtypes (6): atypical glycine encephalopathy, neonatal glycine encephalopathy, infantile glycine encephalopathy, multiple mitochondrial dysfunctions syndrome 7, glycine encephalopathy 1, glycine encephalopathy 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

290 likely benign, 188 uncertain significance, 66 pathogenic, 16 likely pathogenic, 15 pathogenic/likely pathogenic, 13 conflicting classifications of pathogenicity, 12 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1013618	NM_000481.4(AMT):c.602_603del (p.Lys201fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069420	NM_000481.4(AMT):c.259-2A>C	AMT	Pathogenic	criteria provided, single submitter
1070246	NM_000481.4(AMT):c.178C>T (p.Gln60Ter)	AMT	Pathogenic	criteria provided, single submitter
1071338	NM_000481.4(AMT):c.2T>A (p.Met1Lys)	AMT	Pathogenic	criteria provided, single submitter
1071418	NM_000481.4(AMT):c.317T>C (p.Ile106Thr)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
1071928	NM_000481.4(AMT):c.609dup (p.Phe204fs)	AMT	Pathogenic	criteria provided, single submitter
1072385	NM_000481.4(AMT):c.168_171del (p.Leu57fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075196	NM_000481.4(AMT):c.257dup (p.Thr87fs)	AMT	Pathogenic	criteria provided, single submitter
1076854	NM_001164710.2(AMT):c.340-552del	AMT	Pathogenic	criteria provided, single submitter
1163247	NM_000481.4(AMT):c.657dup (p.Val220fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11976	NM_000481.4(AMT):c.125A>G (p.His42Arg)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11978	NM_000481.4(AMT):c.826G>C (p.Asp276His)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
11979	NM_000481.4(AMT):c.959G>A (p.Arg320His)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
11980	NM_000481.4(AMT):c.574C>T (p.Gln192Ter)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11981	NM_000481.4(AMT):c.878-1G>A	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
1357114	NM_000481.4(AMT):c.224del (p.His75fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398467	NM_000481.4(AMT):c.847C>T (p.Pro283Ser)	AMT	Pathogenic	criteria provided, single submitter
1405893	NM_000481.4(AMT):c.221del (p.Gln74fs)	AMT	Pathogenic	criteria provided, single submitter
1447287	NM_000481.4(AMT):c.46C>T (p.Gln16Ter)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452651	NM_000481.4(AMT):c.819T>A (p.Tyr273Ter)	AMT	Pathogenic	criteria provided, single submitter
1000783	NM_004483.5(GCSH):c.338_342del (p.Tyr113fs)	GCSH	Pathogenic	criteria provided, single submitter
1023159	NC_000016.9:g.(?81121196)(81129883_?)del	GCSH	Pathogenic	criteria provided, single submitter
1052188	NM_000170.3(GLDC):c.1852G>A (p.Gly618Arg)	GLDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066463	NM_000170.3(GLDC):c.2678C>T (p.Pro893Leu)	GLDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070375	NC_000009.11:g.(?6602089)(6620339_?)del	GLDC	Pathogenic	criteria provided, single submitter
1070376	NC_000009.11:g.(?6587131)(6610366_?)del	GLDC	Pathogenic	criteria provided, single submitter
1070377	NC_000009.11:g.(?6587131)(6595129_?)del	GLDC	Pathogenic	criteria provided, single submitter
1070959	NM_000170.3(GLDC):c.861+2T>A	GLDC	Pathogenic	criteria provided, single submitter
1071227	NM_000170.3(GLDC):c.586del (p.Leu196fs)	GLDC	Pathogenic	criteria provided, single submitter
1071673	NM_000170.3(GLDC):c.862-5_883del	GLDC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AMT	Definitive	Autosomal recessive	glycine encephalopathy	8
GLDC	Definitive	Autosomal recessive	glycine encephalopathy	8
GCSH	Supportive	Autosomal recessive	neonatal glycine encephalopathy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCSH	Orphanet:289857	Neonatal glycine encephalopathy
GCSH	Orphanet:289860	Infantile glycine encephalopathy
GCSH	Orphanet:289863	Atypical glycine encephalopathy
GLDC	Orphanet:289857	Neonatal glycine encephalopathy
GLDC	Orphanet:289860	Infantile glycine encephalopathy
GLDC	Orphanet:289863	Atypical glycine encephalopathy
AMT	Orphanet:289857	Neonatal glycine encephalopathy
AMT	Orphanet:289860	Infantile glycine encephalopathy
AMT	Orphanet:289863	Atypical glycine encephalopathy
PCDH19	Orphanet:33069	Dravet syndrome
PCDH19	Orphanet:714652	PCDH19 clustering epilepsy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCSH	HGNC:4208	ENSG00000140905	P23434	Glycine cleavage system H protein, mitochondrial	gencc,clinvar
GLDC	HGNC:4313	ENSG00000178445	P23378	Glycine dehydrogenase (decarboxylating), mitochondrial	gencc,clinvar
AMT	HGNC:473	ENSG00000145020	P48728	Aminomethyltransferase, mitochondrial	gencc,clinvar
TCTA	HGNC:11692	ENSG00000145022	P57738	T-cell leukemia translocation-altered gene protein	clinvar
PCDH19	HGNC:14270	ENSG00000165194	Q8TAB3	Protocadherin-19	clinvar
NICN1	HGNC:18317	ENSG00000145029	Q9BSH3	Nicolin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCSH	Glycine cleavage system H protein, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
GLDC	Glycine dehydrogenase (decarboxylating), mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
AMT	Aminomethyltransferase, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
TCTA	T-cell leukemia translocation-altered gene protein	May be required for cellular fusion during osteoclastogenesis.
PCDH19	Protocadherin-19	Calcium-dependent cell-adhesion protein.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	3	6.0×	0.019
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCSH	Enzyme (other)	yes	1.4.1.27	Biotin_lipoyl, GCV_H, 2-oxoA_DH_lipoyl-BS
GLDC	Enzyme (other)	yes	1.4.1.27	ArAA_b-elim_lyase/Thr_aldolase, GcvP, PyrdxlP-dep_Trfase_major
AMT	Enzyme (other)	yes	1.4.1.27	GCVT_N, GcvT, GcvT_C
TCTA	Other/Unknown	no		TCTA
PCDH19	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
NICN1	Other/Unknown	no		Nicolin-1

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
C1 segment of cervical spinal cord	1
amygdala	1
substantia nigra	1
nephron tubule	1
right uterine tube	1
adenohypophysis	1
right adrenal gland	1
right lobe of thyroid gland	1
cortical plate	1
entorhinal cortex	1
middle temporal gyrus	1
frontal cortex	1
prefrontal cortex	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCSH	134	ubiquitous	marker	C1 segment of cervical spinal cord, substantia nigra, amygdala
GLDC	216	broad	marker	right lobe of liver, liver, nephron tubule
AMT	140	broad	yes	right lobe of liver, liver, right uterine tube
TCTA	282	ubiquitous	marker	right adrenal gland, right lobe of thyroid gland, adenohypophysis
PCDH19	175	broad	marker	cortical plate, entorhinal cortex, middle temporal gyrus
NICN1	140	ubiquitous	marker	prefrontal cortex, superior frontal gyrus, frontal cortex

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLDC	2,559
GCSH	2,079
AMT	1,716
PCDH19	1,130
NICN1	492
TCTA	286

Intra-cohort edges

A	B	Sources
AMT	GCSH	string_interaction
AMT	GLDC	string_interaction
GCSH	GLDC	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCSH	P23434	3
GLDC	P23378	3
AMT	P48728	2
PCDH19	Q8TAB3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NICN1	Q9BSH3	80.24
TCTA	P57738	66.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycine degradation	3	978.9×	6e-09	GCSH, GLDC, AMT
Protein lipoylation	1	207.6×	0.010	GCSH
Formation of the nephric duct	1	126.9×	0.010	PCDH19
Carboxyterminal post-translational modifications of tubulin	1	47.6×	0.021	NICN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine decarboxylation via glycine cleavage system	3	3370.4×	1e-10	GCSH, GLDC, AMT
glycine catabolic process	2	3370.4×	3e-07	GLDC, AMT
response to methylamine	1	3370.4×	9e-04	GLDC
response to lipoic acid	1	1685.2×	0.001	GLDC
osteoclast fusion	1	561.7×	0.003	TCTA
negative regulation of osteoclast differentiation	1	108.7×	0.014	TCTA
cellular response to leukemia inhibitory factor	1	31.8×	0.039	GLDC
homophilic cell-cell adhesion	1	28.1×	0.039	PCDH19
cell adhesion	1	7.5×	0.127	PCDH19

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 0 of 6 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCSH	0	0
GLDC	0	0
AMT	0	0
TCTA	0	0
PCDH19	0	0
NICN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCSH	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)
GLDC	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)
AMT	1.4.1.27, 2.1.2.10	glycine cleavage system, aminomethyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	GCSH, GLDC, AMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TCTA, PCDH19, NICN1

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GCSH	0	—
GLDC	0	—
AMT	0	—
TCTA	0	—
PCDH19	0	—
NICN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan