glycine N-methyltransferase deficiency

Summary

glycine N-methyltransferase deficiency (MONDO:0011698) is a disease caused by GNMT (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GNMT (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glycine N-methyltransferase deficiency
Mondo ID	MONDO:0011698
OMIM	606664
Orphanet	289891
DOID	DOID:0111037
ICD-11	16192453
SNOMED CT	763720007
UMLS	C1847720
MedGen	338300
GARD	0010764
Is cancer (heuristic)	no

Also known as: Glycine N-methyltransferase deficiency · glycine N-methyltransferase deficiency · GNMT deficiency · hypermethioninemia due to glycine N-methyltransferase deficiency · hypermethioninemia due to GNMT deficiency

Data availability: 5 ClinVar variants · 4 GenCC gene-disease records.

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 › disorder of methionine catabolism › glycine N-methyltransferase deficiency

Related subtypes (2): hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, adenosine kinase deficiency

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

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
218931	NM_018960.6(GNMT):c.422A>G (p.Asn141Ser)	CNPY3-GNMT	Pathogenic	no assertion criteria provided
4169	NM_018960.6(GNMT):c.149T>C (p.Leu50Pro)	CNPY3-GNMT	Pathogenic	no assertion criteria provided
3254629	NM_018960.6(GNMT):c.452-2_467delinsTGGTCC	CNPY3-GNMT	Uncertain significance	criteria provided, single submitter
4170	NM_018960.6(GNMT):c.529C>A (p.His177Asn)	CNPY3-GNMT	Uncertain significance	criteria provided, single submitter
4279717	NM_018960.6(GNMT):c.546C>A (p.His182Gln)	CNPY3-GNMT	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
GNMT	Strong	Autosomal recessive	glycine N-methyltransferase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNMT	Orphanet:289891	Hypermethioninemia due to glycine N-methyltransferase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNMT	HGNC:4415	ENSG00000124713	Q14749	Glycine N-methyltransferase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNMT	Glycine N-methyltransferase	Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy), a reaction regulated by the binding of 5-methyltetrahydrofo…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNMT	Enzyme (other)	yes	2.1.1.20	Gly/Sar_N_MeTrfase, SAM-dependent_MTases_sf, Methyltransf_25

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNMT	164	tissue_specific	marker	body of pancreas, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNMT	1,154

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNMT	Q14749	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	1427.5×	0.002	GNMT
Glyoxylate metabolism and glycine degradation	1	761.3×	0.002	GNMT
Developmental Lineage of Pancreatic Acinar Cells	1	300.5×	0.003	GNMT

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
obsolete sarcosine metabolic process	1	16852.0×	5e-04	GNMT
obsolete S-adenosylhomocysteine metabolic process	1	8426.0×	5e-04	GNMT
S-adenosylmethionine metabolic process	1	5617.3×	5e-04	GNMT
L-methionine metabolic process	1	2808.7×	8e-04	GNMT
regulation of gluconeogenesis	1	1123.5×	0.001	GNMT
one-carbon metabolic process	1	1123.5×	0.001	GNMT
glycogen metabolic process	1	526.6×	0.002	GNMT
protein homotetramerization	1	237.3×	0.005	GNMT
methylation	1	170.2×	0.006	GNMT

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNMT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GNMT	6	ADMET:3, Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNMT	2.1.1.20	glycine N-methyltransferase

Pharmacogenomics

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNMT	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.