The NM_000156.6:c.505T>A variant in GAMT is a missense variant predicted to cause substitution of a cysteine by tyrosine at amino acid 169 (p.Cys169Tyr). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). These individuals were homozygous for the variant (1pt, PM3) (PMID: 15651030, PMID: 24415674, PMID: 24268530, PMID: 24268530). One of the individuals reported showed deficient (<5% wild-type) GAMT activity in lymphoblasts and elevated GAA in plasma and elevated GAA in urine (PMID: 15651030); one individual showed absent creatine peak on brain MRS and elevated urine GAA (PMID: 24415674); and one individual showed absent creatine peak on brain MRS (PMID: 32606525) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (2/34566 alleles) in the Latino/Admixed American 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 GAMT-deficient fibroblasts 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 0.754 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: 8304, 2 star review status) with 2 submitters classifying the variant as pathogenic and 3 submitters classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely 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 1.1.0): PS3_Supporting, PM2_Supporting, PM3, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)