Glycine encephalopathy 2

Summary

Glycine encephalopathy 2 (MONDO:0958192) is a disease caused by AMT (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: AMT (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glycine encephalopathy 2
Mondo ID	MONDO:0958192
OMIM	620398
DOID	DOID:0061001
UMLS	C5830559
MedGen	1841195
GARD	0026967
Is cancer (heuristic)	no

Data availability: 46 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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 › glycine encephalopathy 2

Related subtypes (5): atypical glycine encephalopathy, neonatal glycine encephalopathy, infantile glycine encephalopathy, multiple mitochondrial dysfunctions syndrome 7, glycine encephalopathy 1

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

46 retrieved; paginated sample, class counts are floors:

14 pathogenic/likely pathogenic, 10 likely pathogenic, 9 pathogenic, 7 conflicting classifications of pathogenicity, 4 uncertain significance, 2 benign/likely 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
1072385	NM_000481.4(AMT):c.168_171del (p.Leu57fs)	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
2975215	NM_000481.4(AMT):c.250_251del (p.Met84fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081728	NM_000481.4(AMT):c.1042del (p.Thr348fs)	AMT	Pathogenic	criteria provided, single submitter
430735	NM_000481.4(AMT):c.350C>T (p.Ser117Leu)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
550886	NM_000481.4(AMT):c.794G>A (p.Arg265His)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551285	NM_000481.4(AMT):c.212A>C (p.His71Pro)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552860	NM_000481.4(AMT):c.664C>T (p.Arg222Cys)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
556278	NM_000481.4(AMT):c.958C>T (p.Arg320Cys)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556661	NM_000481.4(AMT):c.793C>T (p.Arg265Cys)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557814	NM_000481.4(AMT):c.280C>T (p.Arg94Trp)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56232	NM_000481.4(AMT):c.452_466del (p.Lys151_Leu155del)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56233	NM_000481.4(AMT):c.471+2T>C	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
56235	NM_000481.4(AMT):c.59del (p.Pro20fs)	AMT	Pathogenic	criteria provided, single submitter
962887	NM_000481.4(AMT):c.1107_1108del (p.Tyr369_Ser370delinsTer)	AMT	Pathogenic	criteria provided, multiple submitters, no conflicts
969545	NM_000481.4(AMT):c.996dup (p.His333fs)	AMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
594847	NM_000481.4(AMT):c.14dup (p.Ser6fs)	NICN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028287	NM_000481.4(AMT):c.696G>A (p.Glu232=)	AMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323886	NM_000481.4(AMT):c.472-2A>T	AMT	Likely pathogenic	criteria provided, single submitter
2196863	NM_000481.4(AMT):c.697-1G>A	AMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441374	NM_000481.4(AMT):c.339+2T>C	AMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589445	NM_000481.4(AMT):c.697-2A>G	AMT	Likely pathogenic	criteria provided, single submitter
3589446	NM_000481.4(AMT):c.683_684del (p.Glu228fs)	AMT	Likely pathogenic	criteria provided, single submitter
3589447	NM_000481.4(AMT):c.627del (p.Met210fs)	AMT	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMT	Orphanet:289857	Neonatal glycine encephalopathy
AMT	Orphanet:289860	Infantile glycine encephalopathy
AMT	Orphanet:289863	Atypical glycine encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AMT	HGNC:473	ENSG00000145020	P48728	Aminomethyltransferase, mitochondrial	gencc,clinvar
NICN1	HGNC:18317	ENSG00000145029	Q9BSH3	Nicolin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMT	Aminomethyltransferase, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMT	Enzyme (other)	yes	1.4.1.27	GCVT_N, GcvT, GcvT_C
NICN1	Other/Unknown	no		Nicolin-1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
right uterine tube	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
AMT	140	broad	yes	right lobe of liver, liver, right uterine tube
NICN1	140	ubiquitous	marker	prefrontal cortex, superior frontal gyrus, frontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMT	1,716
NICN1	492

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMT	P48728	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NICN1	Q9BSH3	80.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycine degradation	1	815.7×	0.002	AMT
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.008	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine catabolic process	1	8426.0×	2e-04	AMT
glycine decarboxylation via glycine cleavage system	1	5617.3×	2e-04	AMT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
AMT	0	0
NICN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMT	1.4.1.27, 2.1.2.10	glycine cleavage system, aminomethyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	AMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NICN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMT	0	—
NICN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.