GAMT

protein-coding

guanidinoacetate N-methyltransferase, the group of 7BS small molecule methyltransferases

Gene summary

The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

MANE transcript

NM_000156.6

Inheritance

ClinVar variants

P:144U:239B:163

Top phenotype

Cerebral creatine deficiency syndrome 2 (Guanidinoacetate methyltransferase deficiency)

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr19:1,397,026-1,401,570

External References & Databases

Ensembl (ENSG00000130005)

Transcript & Mutation Effects

hg38 • Region Span ~4.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

guanidinoacetate methyltransferase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: Orphanet

guanidinoacetate methyltransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: Labcorp Genetics (formerly Invitae)

guanidinoacetate methyltransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: ClinGen

GAMT was first reported in relation to GAMT deficiency in 1994 (Stöckler et al, PMID 7808840; Stöckler et al, 1996, PMID 8651275). GAMT deficiency is inherited in an autosomal recessive manner. At least 120 cases have been reported worldwide (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). Evidence supporting this gene-disease relationship includes case-level and experimental data. Eleven unique variants (nonsense, frameshift, splice site, and missense) in 9 probands were curated (Stöckler et al, 1996, PMID 8651275; Carducci et al, 2000, PMID 11136556; Schulze, 2003, PMID 12557293; Item et al, 2004, PMID 15108290; Leuzzi et al, 2006, PMID 16293431; Verbruggen et al, 2007, PMID 17466557). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, common variants include p.Trp20Ser (c.59G>C) and c.327G>A (impacting splicing by altering the last nucleotide of exon 2) (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the function of GAMT in creatine synthesis (see Schulze, 2003, PMID 12701824 for review), functional analysis of missense variation in GAMT (Mercimek-Mahmatoglu et al, 2014, PMID 2441567), rescue of GAMT activity by expression of the cDNA in cultured fibroblasts from a patient with GAMT deficiency (Almeida et al, 2006, PMID 16899382), and the biochemical features and impact of creatine supplementation in a GAMT knockout mouse model (Schmidt et al, 2004, 15028668; Iqbal et al, 2018, PMID 28808834). More experimental evidence may be available but the maximum score (6 points) has been reached. In summary, GAMT is definitively associated with GAMT deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Aminoacidopathies GCEP on January 25th, 2019.

guanidinoacetate methyltransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: G2P

guanidinoacetate methyltransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: Ambry Genetics

guanidinoacetate methyltransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: Natera

guanidinoacetate methyltransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012999

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cerebral creatine deficiency syndrome 2 (Guanidinoacetate methyltransferase deficiency)AR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: The condition involves neurologic sequelae, and medical (eg, with creatine-monohydrate, L-ornithine, and/or sodium benzoate) as well as dietary (eg, with ornithine supplementation and protein/arginine restriction) has been reported to increase cerebral creatine, resulting in improvement or stabilization of clinical manifestations in all symptomatic individuals

Refs: 7808840; 8651275; 9386672; 11196109; 15651030; 17171576; 17336114; 19027335; 20301745; 23031365; 24268530; 34389248

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GAMT variants in ClinVar

11 Conditions Cataloged

Cerebral creatine deficiency syndromeTotal: 534

Deficiency of guanidinoacetate methyltransferaseTotal: 255

not providedTotal: 152

Inborn genetic diseasesTotal: 98

not specifiedTotal: 58

GAMT-related disorderTotal: 34

Intellectual disabilityTotal: 2

Parkinson disease, late-onsetTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000156.6. 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	1 clinvar	1 clinvar	11 clinvar	149 clinvar	2 clinvar	164
missense	14 clinvar	25 clinvar	222 clinvar	8 clinvar	4 clinvar	273
nonsense	15 clinvar	11 clinvar	2 clinvar			28
start loss	2 clinvar	2 clinvar				4
frameshift	26 clinvar	29 clinvar	3 clinvar			58
splice donor/acceptor (+/-2bp)	4 clinvar	14 clinvar	1 clinvar			19
Total	62	82	239	157	6	546

Highest pathogenic variant AF is 0.00045182844

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000156.6	RefSeq	NP_000147.1	6	MANE Select
ENST00000252288.8	Ensembl	ENSP00000252288.1	6	MANE Select
NM_138924.3	RefSeq	NP_620279.1	5	Standard
ENST00000447102.8	Ensembl	ENSP00000403536.2	5	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
muscle contraction
spermatogenesis
animal organ morphogenesis

Molecular Function

methyltransferase activity
S-adenosylmethionine-dependent methyltransferase activity
guanidinoacetate N-methyltransferase activity

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447102
Coding exons: 5
Length: 4479
Individuals with no LoFs: 125517
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125525
p: 0.0000319

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0872	153	150	1.02	0.00000858	1699
Missense (PolyPhen)		46	46.021	0.99954		506
Synonymous	0.0246	64	64.3	0.996	0.00000399	550
Loss of Function	1.11	4	7.24	0.553	3.11e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts guanidinoacetate to creatine, using S- adenosylmethionine as the methyl donor (PubMed:26003046, PubMed:24415674, PubMed:26319512). Important in nervous system development (PubMed:24415674). {ECO:0000269|PubMed:24415674, ECO:0000269|PubMed:26003046, ECO:0000269|PubMed:26319512}.;

Recessive Scores

pRec: 0.189

Intolerance Scores

LoFtool: 0.140
RVIS EVS: -0.09
RVIS percentile EVS: 46.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

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