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…

LOFmechanismARLOEUF 1.261 OMIM phenotype

VCEP Guidelines: Cerebral Creatine DeficiencyReleased

View Specifications ClinGen Panel

Clinical Summary— GAMT

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Gene-Disease Validity (ClinGen)

guanidinoacetate methyltransferase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

127 unique Pathogenic / Likely Pathogenic· 221 VUS of 613 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGAMT-related guanidinoacetate methyltransferase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7131th %ile

GOF

0.5563th %ile

LOF

0.2091th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

613 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic72

VUS221

Likely Benign241

Benign17

Conflicting2

Pathogenic

Likely Pathogenic

221

VUS

241

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	16	3	1	55
Likely Pathogenic	44	25	3	0	72
VUS	3	187	20	11	221
Likely Benign	1	15	85	140	241
Benign	0	5	9	3	17
Conflicting	—				2
Total	83	248	120	155	608

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

24 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap GAMT — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →