GAMT p.Ala74Pro

The NM_000156.6:c.220G>C variant in GAMT is predicted to result in a missense substitution of alanine by proline at amino acid 74 (p.Ala74Pro). This variant has been identified in two unrelated probands with clinical features consistent with GAMT deficiency; one with absent creatine peak on MRS, the other with deficient GAMT activity. Both had urine guanidinoacetate levels 1.1 - 12 times above the upper limit of reference range, but specific values for each patient were not provided (PMID: 24415674) (PP4_Moderate). One of these individuals was reported to be compound heterozygous, phase unconfirmed, for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A (ClinVar Variation ID: 21065) (0.5 points) and another patient was homozygous for the variant (0.5 points) (PMID: 24415674) Total 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000033945 (4/1178374 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.930 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase 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): PM3, PP3_Moderate, PP4_Moderate PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 15, 2025)