The NM_000156.6:c.590T>C variant in GAMT is a missense variant predicted to cause substitution of leucine by proline at amino acid 197 (p.Leu197Pro). This variant has been detected in two unrelated individuals with elevated guanidinoacetate with low creatine in both plasma and urine; in addition, one of these individuals had a brain MRS which revealed no creatine peak (PMID: 16293431, 19288536) (PP4_Strong). One of these patients was reported to be compound heterozygous for the variant and another variant in GAMT that has been classified as likely pathogenic by the ClinGen CCDS VCEP, c.526delG; the phase was confirmed by parental testing (PMID: 19288536, 19461121) (1 point). Another patient was reported to be homozygous for the variant PMID: 16293431 (0.5 points). Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00000339 (4/1179854 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in a GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.925 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: 2570638). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 10, 2025)