Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

CA402994686

1335317 (ClinVar)

Gene: GAMT (HGNC:2593)

Condition: guanidinoacetate methyltransferase deficiency (MONDO:0012999)

Inheritance Mode: Autosomal recessive inheritance

UUID: 7ed0a7a6-a85c-4faf-8a42-5ac1a5559d6b

Approved on: 2026-04-21

Published on: 2026-04-21

HGVS expressions

NM_000156.6:c.476T>C

NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

NC_000019.10:g.1399010A>G

CM000681.2:g.1399010A>G

NC_000019.9:g.1399009A>G

CM000681.1:g.1399009A>G

NC_000019.8:g.1350009A>G

NG_009785.1:g.7544T>C

ENST00000252288.8:c.476T>C

ENST00000447102.8:c.476T>C

ENST00000591788.3:c.159T>C

ENST00000640164.1:n.309T>C

ENST00000640762.1:c.407T>C

ENST00000252288.6:c.476T>C

ENST00000447102.7:c.476T>C

ENST00000591788.2:c.161T>C

NM_000156.5:c.476T>C

NM_138924.2:c.476T>C

NM_138924.3:c.476T>C

Likely Pathogenic

PM3_Supporting PP3_Strong PP4_Moderate PM2_Supporting PS3_Supporting

Evidence Links 1

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.476T>C variant in GAMT is predicted to result in the substitution of leucine by proline at amino acid 159 (p.Leu159Pro). This variant has been identified in one homozygous individual with an absent creatine peak on brain MRS and elevated urine guanidinoacetate (value not provided) (PM3_Supporting, PP4_Moderate) (PMID: 24415674). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.947 which is above the threshold of 0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong). This variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PP3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting (Classification approved by the ClinGen CCDS VCEP on April 21, 2026)

PM3_Supporting

PMID: 24415674: Identified in one homozygous proband (0.5pts)

PP3_Strong

The computational predictor REVEL gives a score of 0.947 which is above the threshold of 0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong).

PP4_Moderate

One proband who is homozygous for the variant has clinical symptoms consistent with GAMT deficiency, showed an absent creatine peak on brain MRS (3pts) (PMID: 24415674) (PP4_Moderate).

PM2_Supporting

The variant is absent in gnomAD v4.1.0. (PM2_Supporting)

PS3_Supporting

PMID: 24415674: Variant shown to result in undetectable GAMT enzymatic activity when expressed in GAMT-deficient fibroblasts

PMID: 24415674: Variant shown to result in undetectable GAMT enzymatic activity when expressed in GAMT-deficient fibroblasts PubMed:24415674

Curation History

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