GAMT p.Ala196Val

The NM_000156.6:c.587C>T variant in GAMT is a missense variant that is predicted to cause the substitution of an alanine by a valine at amino acid position 196 (p.Ala196Val). This variant has been previously reported as a heterozygous variant detected in the context of newborn screening in Dutch newborns (PMID: 26319512). Expression of the variant in GAMT-deficient fibroblasts resulted in similar activity as wild type GAMT indicating that this variant does not impact protein function (PMID: 26319512) (BS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001043 (123/1179840 alleles; no homozygotes) 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 0.267 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205588). Although there is conflicting evidence, with two benign criteria met (BP4 and BS3_Supporting) and one pathogenic criterion met (PM2_Supporting), the consensus from the ClinGen CCDS VCEP is that this variant is likely benign for GAMT deficiency, based upon the in silico and functional evidence. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BS3_Supporting, BP4 (classification modified to likely benign) (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024)