The NM_000156.6:c.491G>A variant in GAMT is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 164 (p.Gly164Asp). There has been one reported case in literature with this variant; this patient had elevated plasma guanidinoacetate levels on two occasions and is compound heterozygous for the variant and a pathogenic variant in GAMT, c.522G>A (p.Trp174Ter), confirmed in trans by parental testing (PP4, PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34562 alleles) in the Latino 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 0.919 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 203539). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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, PP4, PP3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).