The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global developmental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID: 24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID: 24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency (MAF) in gnomAD v4.1.0 is 0.002564 (10/3900 alleles) in the Middle Eastern population; there is one homozygote in the European non-Finnish population, in gnomAD v4.1.0. While the MAF is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), PM2_Supporting is not met due to presence of a homozygote. Because GAMT deficiency is a severe, pediatric onset condition, the presence of a homozygote supports benignity (BS2). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 2.0.0.): BS2, BS3_Supporting (Classification approved by the ClinGen Cerebral Creatine Deficiencies VCEP on October 8, 2025)