GATM

protein-coding

glycine amidinotransferase

Gene summary

This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001482.3

Inheritance

AR, AD

ClinVar variants

P:40U:275B:160

Top phenotype

Fanconi renotubular syndrome 1; Cerebral creatine deficiency syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr15:45,361,124-45,402,327

External References & Databases

Ensembl (ENSG00000171766)

Transcript & Mutation Effects

hg38 • Region Span ~41.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

AGAT deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: PanelApp Australia

AGAT deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: G2P

AGAT deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: Ambry Genetics

Fanconi renotubular syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024525

Submitter: PanelApp Australia

primary Fanconi syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007600

Submitter: Orphanet

AGAT deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: ClinGen

The relationship between GATM and arginine:glycine amidinotransferase (AGAT) deficiency, an autosomal recessive disorder of creatine metabolism, was evaluated using the ClinGen Clinical Validity Framework as of February 6th, 2019. Variants in GATM were first reported in humans with this disorder in 2001 (Item et al, PMID 11555793) in two sisters previously reported with creatine deficiency in the brain (Bianchi et al, 2000; PMID 10762163). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 7 unique variants (missense, nonsense, frameshift, and splice site) have been reported in 6 probands in 5 publications (Edvardson et al, 2010, PMID 20682460; Verma et al, 2010, PMID 20625172; Ndika et al, 2012, PMID 22386973; Nouioua et al, 2013, PMID 23770102; Stockler-Ipsiroglu et al, 2015, PMID 26490222). Variants in this gene segregated with disease in 3 additional family members in one large family (Battini et al, 2002, PMID 12468279). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of AGAT, catalyzing the first step of creatine synthesis, functional analysis of missense variants (Des Roches et al, 2016, PMID 27233232), and the biochemical features and clinical features of a null mouse model (Choe et al, 2013, PMID 23026748; Nabuurs et al, 2015, PMID 23129796; Iqbal et al, PMID 28808834). In summary, GATM is definitively associated with AGAT deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in renal Fanconi syndrome and kidney failure. That gene-disease relationship will be assessed separately.

AGAT deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: Orphanet

Fanconi renotubular syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024525

Submitter: ClinGen

GATM was first reported in relation to autosomal dominant in Fanconi renotubular syndrome in 2018 (Reichold et al., PMID: 29654216). This condition is characterized by chronic kidney disease (which often progresses to end-stage renal disease); hypokalemia; hypophosphatemia; metabolic acidosis; urine anomalies (glycosuria; aminoaciduria; and proteinuria); osteomalacia; and other skeletal anomalies (such as osteoporosis). Eight variants (all missense) that have been reported in at least ten probands in six publications (PMIDs: 29654216, 36148635, 37286521, 38310177, 38876250, 39544690) are included in this curation. The mechanism of pathogenicity is reported to be gain-of-function (PMIDs: 29654216). Heterozygous GATM variants in a specific region of the protein, approximately residues 290-350, result in the production of a de novo surface for interaction, leading to aggregates of multimers within mitochondria (PMID: 29654216). This gene-disease relationship is also supported by experimental evidence (expression, functional alteration, biochemical function, and rescue evidence; PMID: 29654216). GATM is expressed in proximal renal tubule cells. Rescue evidence revealed that creatine supplementation decreased expression of the gene in mice. Other experimental evidence showed that GATM is key in creatine biosynthesis, and that GATM mutants lead to protein aggregates in mitochondria. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 2/18/2026 (SOP Version 12).

Fanconi renotubular syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024525

Submitter: Natera

AGAT deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: Natera

Fanconi renotubular syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024525

Submitter: Ambry Genetics

AGAT deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012996

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Fanconi renotubular syndrome 1; Cerebral creatine deficiency syndrome 3AD/AR

Manifestation: Biochemical; Neurologic; Renal

Intervention: Biochemical; Renal

Rationale: In Fanconi renotubular syndrome 1, individuals manifest with renal disease, and awareness may allow prompt management to help manage sequelae, and there is some evidence that creatine supplementation may be beneficial; In Cerebral creatine deficiency syndrome 3, treatment with oral creatine has been reported to possibly increase cerebral creatine, resulting in improved cognitive development

Refs: 10762163; 11555793; 12468279; 16769397; 20301745; 20682460; 22386973; 23660394; 29654216

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GATM variants in ClinVar

11 Conditions Cataloged

Arginine:glycine amidinotransferase deficiencyTotal: 574

Fanconi renotubular syndrome 1Total: 86

not providedTotal: 73

Inborn genetic diseasesTotal: 56

not specifiedTotal: 36

GATM-related disorderTotal: 11

GATM-related disordersTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001482.3. 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			8 clinvar	148 clinvar	3 clinvar	159
missense	1 clinvar	9 clinvar	264 clinvar	6 clinvar	3 clinvar	283
nonsense	8 clinvar	5 clinvar	1 clinvar			14
start loss						0
frameshift	7 clinvar	3 clinvar	2 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar				7
Total	17	23	275	154	6	475

Highest pathogenic variant AF is 0.000006572893

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001482.3	RefSeq	NP_001473.1	9	MANE Select
ENST00000396659.8	Ensembl	ENSP00000379895.3	9	MANE Select
NM_001321015.2	RefSeq	NP_001307944.1	7	Standard
ENST00000558118.1	Ensembl	ENSP00000452971.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Glycine, serine and threonine metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Hyperornithinemia with gyrate atrophy (HOGA)
Creatine deficiency, guanidinoacetate methyltransferase deficiency

Biological Process

creatine metabolic process
creatine biosynthetic process
multicellular organism development
learning or memory
muscle atrophy

Molecular Function

amidinotransferase activity
glycine amidinotransferase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396659
Coding exons: 9
Length: 41204
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.29	144	245	0.588	0.0000135	2772
Missense (PolyPhen)		35	92.381	0.37887		936
Synonymous	0.609	75	82.0	0.915	0.00000446	806
Loss of Function	3.29	7	24.6	0.284	0.00000147	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the biosynthesis of guanidinoacetate, the immediate precursor of creatine. Creatine plays a vital role in energy metabolism in muscle tissues. May play a role in embryonic and central nervous system development. May be involved in the response to heart failure by elevating local creatine synthesis. {ECO:0000269|PubMed:16125225, ECO:0000269|PubMed:16614068, ECO:0000269|PubMed:16820567}.;
Disease: DISEASE: Cerebral creatine deficiency syndrome 3 (CCDS3) [MIM:612718]: An autosomal recessive disorder characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. {ECO:0000269|PubMed:11555793, ECO:0000269|PubMed:20682460, ECO:0000269|PubMed:22386973, ECO:0000269|PubMed:23660394, ECO:0000269|PubMed:23770102, ECO:0000269|PubMed:26490222, ECO:0000269|PubMed:27233232}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.207

Intolerance Scores

LoFtool: 0.383
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.521

Gene Damage Prediction

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