Guanidinoacetate methyltransferase deficiency

Summary

Guanidinoacetate methyltransferase deficiency (MONDO:0012999) is a disease caused by GAMT (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GAMT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 269
• Phenotypes (HPO): 22
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0007153	Progressive extrapyramidal movement disorder	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002305	Athetosis	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002457	Abnormal head movements	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)
HP:0001252	Hypotonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	guanidinoacetate methyltransferase deficiency
Mondo ID	MONDO:0012999
MeSH	C537622
OMIM	612736
Orphanet	382
DOID	DOID:0050799
ICD-11	1811642217
SNOMED CT	124239003
UMLS	C0574080
MedGen	154356
GARD	0002578
NORD	1967
Is cancer (heuristic)	no

Also known as: CCDS2 · cerebral creatine deficiency syndrome 2 · cerebral creatine deficiency syndrome type 2 · disorder of guanidinoacetate N-methyltransferase activity · GAMT deficiency · guanidinoacetate methyltransferase deficiency · guanidinoacetate N-methyltransferase activity disease

Data availability: 269 ClinVar variants · 123 ClinGen variant curations · 6 GenCC gene-disease records · 9 cell lines.

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 › cerebral creatine deficiency syndrome › guanidinoacetate methyltransferase deficiency

Related subtypes (2): creatine transporter deficiency, AGAT 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

269 retrieved; paginated sample, class counts are floors:

119 uncertain significance, 53 likely pathogenic, 41 pathogenic, 24 likely benign, 16 pathogenic/likely pathogenic, 13 benign, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3766440	NM_000156.6(GAMT):c.[1A>G];[327G>A]		Pathogenic	criteria provided, single submitter
1069228	NM_000156.6(GAMT):c.59G>A (p.Trp20Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070918	NM_000156.6(GAMT):c.356dup (p.Asp119fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073500	NM_000156.6(GAMT):c.324_325del (p.His108fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073697	NM_000156.6(GAMT):c.307del (p.Ala103fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075552	NM_000156.6(GAMT):c.64del (p.Ala22fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075655	NM_000156.6(GAMT):c.289C>T (p.Gln97Ter)	GAMT	Pathogenic	criteria provided, multiple submitters, no conflicts
1098274	NM_000156.6(GAMT):c.158_181+7del	GAMT	Pathogenic	reviewed by expert panel
1184466	NM_000156.6(GAMT):c.313_314insTG (p.Arg105fs)	GAMT	Pathogenic	no assertion criteria provided
1312506	NM_000156.6(GAMT):c.497T>C (p.Leu166Pro)	GAMT	Pathogenic	reviewed by expert panel
1374768	NM_000156.6(GAMT):c.432_433dup (p.His145fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382497	NM_000156.6(GAMT):c.402C>A (p.Tyr134Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391239	NM_000156.6(GAMT):c.432G>A (p.Trp144Ter)	GAMT	Pathogenic	reviewed by expert panel
1409758	NM_000156.6(GAMT):c.526dup (p.Glu176fs)	GAMT	Pathogenic	reviewed by expert panel
1460109	NM_000156.6(GAMT):c.350G>A (p.Trp117Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705080	NM_000156.6(GAMT):c.475del (p.Leu159fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2003951	NM_000156.6(GAMT):c.332_338del (p.Ile111fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205584	NM_000156.6(GAMT):c.522G>A (p.Trp174Ter)	GAMT	Pathogenic	reviewed by expert panel
2083318	NM_000156.6(GAMT):c.289del (p.Gln97fs)	GAMT	Pathogenic	criteria provided, multiple submitters, no conflicts
21065	NM_000156.6(GAMT):c.327G>A (p.Lys109=)	GAMT	Pathogenic	reviewed by expert panel
2419155	NM_000156.6(GAMT):c.134G>A (p.Trp45Ter)	GAMT	Pathogenic	reviewed by expert panel
2446458	NM_000156.6(GAMT):c.391G>C (p.Gly131Arg)	GAMT	Pathogenic	reviewed by expert panel
2446459	NM_000156.6(GAMT):c.403G>T (p.Asp135Tyr)	GAMT	Pathogenic	reviewed by expert panel
2570638	NM_000156.6(GAMT):c.590T>C (p.Leu197Pro)	GAMT	Pathogenic	reviewed by expert panel
2675837	NM_000156.6(GAMT):c.235C>T (p.Gln79Ter)	GAMT	Pathogenic	reviewed by expert panel
2831012	NM_000156.6(GAMT):c.444_448del (p.Phe149fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064200	NM_000156.6(GAMT):c.403G>C (p.Asp135His)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
328352	NM_000156.6(GAMT):c.133T>A (p.Trp45Arg)	GAMT	Pathogenic	reviewed by expert panel
3583501	NM_000156.6(GAMT):c.418_419del (p.Ser140fs)	GAMT	Pathogenic	reviewed by expert panel
4537499	NM_000156.6(GAMT):c.194T>C (p.Leu65Pro)	GAMT	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
GAMT	Definitive	Autosomal recessive	guanidinoacetate methyltransferase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GAMT	Orphanet:382	Guanidinoacetate 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
GAMT	HGNC:4136	ENSG00000130005	Q14353	Guanidinoacetate N-methyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GAMT	Guanidinoacetate N-methyltransferase	Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.

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)
GAMT	Enzyme (other)	yes	2.1.1.2	GuanidinoAc_N-MeTrfase, RMT2_dom, SAM-dependent_MTases_sf

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
gastrocnemius	1
hindlimb stylopod muscle	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GAMT	258	ubiquitous	marker	hindlimb stylopod muscle, right lobe of liver, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GAMT	2,166

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GAMT	Q14353	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Creatine metabolism	1	1038.2×	0.002	GAMT
Transcriptional Regulation by MECP2	1	317.2×	0.003	GAMT

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
creatine biosynthetic process	1	8426.0×	8e-04	GAMT
creatine metabolic process	1	4213.0×	8e-04	GAMT
regulation of multicellular organism growth	1	648.1×	0.004	GAMT
muscle contraction	1	208.1×	0.007	GAMT
animal organ morphogenesis	1	191.5×	0.007	GAMT
methylation	1	170.2×	0.007	GAMT
spermatogenesis	1	35.2×	0.028	GAMT

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
GAMT	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
GAMT	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAMT	2.1.1.2	guanidinoacetate 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	GAMT
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)
GAMT	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns