The NM_001482.3:c.1237C>T variant in GATM is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 413 (p.Arg413Trp). This variant has been detected in one individual with AGAT deficiency who had low guanidinoacetate in plasma and low to low-normal creatine in plasma, as well as significantly decreased creatine peak on brain MRS (PMID 26490222) (PP4_Strong). This individual was compound heterozygous for the variant and a likely pathogenic variant, and the variants were confirmed in trans by parental testing (PMID 23660394) (PM3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in HeLa cells resulted in 0% wild type AGAT activity (PMID 27233232), indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.585 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. Another missense variant c.1238G>A, (p.Arg413Gln) (PMIDs 23660394, 26490222, 27233232) in the same codon has been classified as likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 598112). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT 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): PP4_Strong, PM3, PM2_Supporting, PS3_Supporting, PM5_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).