The NM_000156.6:c.526dup (p.Glu176GlyfsTer15) variant in GAMT has been previously reported in at least one individual with guanidinoacetate methyltransferase deficiency (PMID: 15108290). This variant is absent in population databases (PM2_Supporting). This variant has been reported in ClinVar (Variation ID: 1409758) and has been interpreted as pathogenic by Invitae. The individual who was previously reported was a compound heterozygote; however, this occurrence was counted for evidence for PM3 for the other variant and thus not used here to prevent circularity in the use of PM3 (PMID: 15108290). This individual showed elevated urinary GAA and partially absent creatine peak and absent GAA peak on brain MRS with full GAMT gene sequencing (PMID: 15108290) (PP4_Strong). The p.Glu176GlyfsTer15 variant is a frameshift variant at amino acid position 176 that is predicted to lead to premature termination 15 amino acids downstream. As the variant results in termination downstream of the last 50 base pairs of the penultimate exon of the GAMT gene, nonsense-mediated decay is not predicted; however, the variant results in removal of >10% of the encoded protein (PVS1_Strong). In summary, this variant meets criteria to be classified as pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PVS1_Strong, PM2_Supporting, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)