The NM_000156.6:c.491dup (p.Val165ArgfsTer26) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong; PMID: 11136556). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in the East Asian population, which is less than the ClinGen CCDS VCEP's threshold (<0.0004) (PM2_Supporting). The variant was found in homozygosity in one patient who meets the ClinGen CCDS VCEP's PP4 specifications (PMID 12557293). This variant was also found in compound heterozygosity in two patients who meet ClinGen CCDS VCEP’s PP4 specifications; one with the variant c.564G>T (p. Met188Ile) (PMID 28438604) or "IVS5-3C>G" (PMID 11136556). However, the in trans data from these two patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). Three patients have been reported with this variant and clinical and biochemical features consistent with GAMT deficiency including an adult patient with low creatine and elevated GAA in urine, plasma, and CSF, <10% normal GAMT activity in fibroblasts, and absent creatine peak with GAA detected on MRS (PMID 12557293), low creatine and elevated GAA in plasma and urine and absent creatine peak on MRS (PMID 28438604), and elevated GAA in plasma, urine, and CSF, and lacking creatine peak on brain MRS (PMID 1136556)(PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 495685) 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): PVS1_Strong, PP4_Strong, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).