The NM_000156.6:c.194T>C variant in GAMT is a missense variant that is predicted to cause the substitution of a leucine by a proline at amino acid position 65 (p.Leu65Pro). This variant has been detected in at least one individual with GAMT deficiency (Lei et al. Journal of Clinical Pediatrics, 2024, 42(12): 1039-1046), who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, c.467C>A (p.Ala156Asp), which was confirmed in trans by parental testing. This occurrence was not counted for PM3 evidence as it was used for PM3 evidence for the c.467C>A (p.Ala156Asp) variant, thereby preventing circularity. The individual with this variant (Lei et al. Journal of Clinical Pediatrics, 2024, 42(12): 1039-1046) had elevated GAA and low or low normal creatine in urine and significantly decreased creatine peak (GAA not reported) on brain MRS (4 points; PP4_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 8.49e-7 (1/1178058 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). The computational predictor REVEL gives a score of 0.981 which is above the threshold of 0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong). There is no ClinVar entry for this variant. 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, PP3_Strong, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 10, 2025)