Submission Details

GAMT was first reported in relation to GAMT deficiency in 1994 (Stöckler et al, PMID 7808840; Stöckler et al, 1996, PMID 8651275). GAMT deficiency is inherited in an autosomal recessive manner. At least 120 cases have been reported worldwide (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). Evidence supporting this gene-disease relationship includes case-level and experimental data. Eleven unique variants (nonsense, frameshift, splice site, and missense) in 9 probands were curated (Stöckler et al, 1996, PMID 8651275; Carducci et al, 2000, PMID 11136556; Schulze, 2003, PMID 12557293; Item et al, 2004, PMID 15108290; Leuzzi et al, 2006, PMID 16293431; Verbruggen et al, 2007, PMID 17466557). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, common variants include p.Trp20Ser (c.59G>C) and c.327G>A (impacting splicing by altering the last nucleotide of exon 2) (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the function of GAMT in creatine synthesis (see Schulze, 2003, PMID 12701824 for review), functional analysis of missense variation in GAMT (Mercimek-Mahmatoglu et al, 2014, PMID 2441567), rescue of GAMT activity by expression of the cDNA in cultured fibroblasts from a patient with GAMT deficiency (Almeida et al, 2006, PMID 16899382), and the biochemical features and impact of creatine supplementation in a GAMT knockout mouse model (Schmidt et al, 2004, 15028668; Iqbal et al, 2018, PMID 28808834). More experimental evidence may be available but the maximum score (6 points) has been reached. In summary, GAMT is definitively associated with GAMT deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Aminoacidopathies GCEP on January 25th, 2019.