The NM_000156.6:c.505T>C variant in GAMT is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 169 (p.Cys169Arg). This variant has been identified in 3 individuals with a diagnosis of GAMT deficiency. One of these individuals had pretreatment marked elevation of guanidinoacetate and low/low normal creatine in plasma, urine, and CSF, and diminished creatine peak on brain MRS (ACD registry). Another proband was reported with elevated guanidinoacetate in plasma (PMID: 23660394, PMID: 24268530) (PP4_Strong). These individuals are all compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP including c.522G>A (p.Trp174Ter) (ClinVar Variation ID: 205584, SCV002600143.1), confirmed in trans by parental testing (PMID: 23660394, PMID: 24268530) (1 point), c.299_311dup (ClinVar Variation ID: 8302, SCV002600154.1) confirmed in trans by parental testing (Association for Creatine Deficiencies registry) (1 point), and c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303, SCV004009593.1), phase unconfirmed (Association for Creatine Deficiencies registry) (0.5 points) (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.828, evidence that correlates with impact to GAMT function (PP3). A different missense variant at the same codon, c.506G>A (p.Cys169Tyr) (ClinVar ID: 8304, SCV004009598.1),has been classified as likely pathogenic by the ClinGen CCDS VCEP (PM5_Supporting) There is a ClinVar entry for this variant (Variation ID: 818179). 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 1.1.0): PM3_Strong, PP4_Strong, PP3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 13, 2024)