GAMT

Chr 19AR

guanidinoacetate N-methyltransferase

Also known as: CCDS2, HEL-S-20, PIG2, TP53I2

NCBI Gene: 2593 ENSG00000130005 UniProt: Q14353 OMIM: 601240

This gene encodes guanidinoacetate N-methyltransferase, which converts guanidinoacetate to creatine using S-adenosylmethionine as the methyl donor. Mutations cause cerebral creatine deficiency syndrome 2, an autosomal recessive disorder characterized by neurologic abnormalities and muscular hypotonia due to creatine deficiency and guanidinoacetate accumulation in the brain. The gene shows tolerance to loss-of-function variants (low constraint), and affected individuals typically present in infancy or early childhood with developmental delays and seizures.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cerebral creatine deficiency syndrome 2MIM #612736

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · guanidinoacetate methyltransferase deficiency · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.26

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — GAMT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.26LOEUF

pLI 0.009

Z-score 1.11

OE 0.55 (0.27–1.26)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.09Z-score

OE missense 1.02 (0.89–1.17)

153 obs / 150.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.55 (0.27–1.26)

0≤0.351.4

Missense OE?1.02 (0.89–1.17)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 4 / 7.2Missense obs/exp: 153 / 150.0Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in GAMT?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 80

544 rare PASS variants

Rare truncating (LoF)

1 in 750

96 rare PASS variants

Rare synonymous (reference)

1 in 290

211 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GAMT. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 690
South Asian	~43k	1 in 110	1 in 1,100
Remaining (unassigned)	~30k	1 in 74	1 in 890
European (Finnish)	~27k	1 in 240	1 in 2,800
Admixed American	~22k	1 in 97	1 in 3,500
African / African American	~21k	1 in 99	1 in 670
East Asian	~20k	1 in 90	1 in 2,200
Ashkenazi Jewish	~13k	1 in 380	1 in 840
Middle Eastern	~2,884	1 in 170	1 in 440

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 6.? see exons ↓