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.520T>C (p.Trp174Arg)

CA304065950

1420866 (ClinVar)

Gene: GAMT (HGNC:2593)

Condition: guanidinoacetate methyltransferase deficiency (MONDO:0012999)

Inheritance Mode: Autosomal recessive inheritance

UUID: 94bbe47d-781a-4378-ba79-2455475b5394

Approved on: 2026-04-21

Published on: 2026-04-21

HGVS expressions

NM_000156.6(GAMT):c.520T>C (p.Trp174Arg)

NM_000156.6:c.520T>C

NC_000019.10:g.1398966A>G

CM000681.2:g.1398966A>G

NC_000019.9:g.1398965A>G

CM000681.1:g.1398965A>G

NC_000019.8:g.1349965A>G

NG_009785.1:g.7588T>C

ENST00000252288.8:c.520T>C

ENST00000447102.8:c.520T>C

ENST00000591788.3:c.203T>C

ENST00000640164.1:n.353T>C

ENST00000640762.1:c.451T>C

ENST00000252288.6:c.520T>C

ENST00000447102.7:c.520T>C

ENST00000591788.2:c.205T>C

NM_000156.5:c.520T>C

NM_138924.2:c.520T>C

NM_138924.3:c.520T>C

Likely Pathogenic

PM2_Supporting PP3_Moderate PP4 PM3

Evidence Links 0

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.520T>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 174 (p.Trp174Arg). Two probands have been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate and low creatine in dried blood spot, and improvement in seizures frequency on creatine treatment (PMID: 35588794) (PP4). One proband was compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.403G>A (p.Asp135Asn) (ClinVar Variation ID: 573140), and confirmed in trans by parental DNA testing (PMID: 35588794) (1 point) (PM3). Another patient was compound heterozygous for the variant and c.444_448del (p.Phe149LeufsTer40) (ClinVar Variation ID: 2831012) (PMID: 35588794). The allelic data from this patient will be used in the classification of the second variant and was not included here to avoid circular logic. In addition a patient with atypical developmental epileptic encephalopathy is homozygous for the variant (PMID: 41751517). However, because no biochemical details are available, no points were given for PM3 for this patient. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000076 (9/1179976 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.808 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 1420866). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM3, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 21, 2026)

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000076 (9/1179976 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).

PP3_Moderate

The computational predictor REVEL gives a score of 0.808 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate).

PP4

Two probands have been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate and low creatine in dried blood spot, and improvement in seizures frequency on creatine treatment (PMID: 35588794) (PP4)

PM3

One proband was compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.403G>A (p.Asp135Asn) (ClinVar Variation ID: 573140), and confirmed in trans by parental DNA testing (PMID: 35588794) (1 point) (PM3). Another patient was compound heterozygous for the variant and c.444_448del (p.Phe149LeufsTer40) (ClinVar Variation ID: 2831012) (PMID: 35588794). The allelic data from this patient will be used in the classification of the second variant and was not included here to avoid circular logic. In addition a patient with atypical developmental epileptic encephalopathy is homozygous for the variant (PMID: 41751517). However, because no biochemical details are available, no points were given for PM3 for this patient.

Curation History

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