The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID: 29302074, PMID: 32214227, PMID: 15234333, PMID: 23660394, PMID: 15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID: 15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID: 15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as 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 1.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)