Submission Details

The relationship between AMT and glycine encephalopathy, an autosomal recessive disorder of the glycine cleavage system, was evaluated using the ClinGen Clinical Validity Framework as of April 6th, 2019. Variants in AMT, which encodes the T-protein (aminomethyltransferase) of the glycine cleavage system, were first reported in humans with this disease as early as 1994 (Nanao et al, PMID 8005589). Variants in AMT have been reported in over 100 cases of glycine encephalopathy (non-ketotic hyperglycinemia, NKH) and include missense, nonsense, frameshift, and splice site variants. Variants in this gene have been reported in about 15-20% of probands with glycine encephalopathy; about 80% of patients have variants in GLDC which encodes the P-protein of the glycine cleavage system (Coughlin et al, 2017, PMID 27362913). Eleven patients with 15 unique variants in AMT are included here (Nanao et al, 1994, PMID 8005589; Azize et al, 2014, PMID 25231368; Swanson et al, 2015, PMID 26179960; Belcastro et al, 2016, PMID 26371980; Gencpinar et al, 2016, PMID 27164344). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Various recurrent variants have been reported, including p.Arg320His (Coughlin et al, 2017, PMID 27362913). The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the T protein (aminomethyltransferase) in the glycine cleavage system (Fujiwara and Motokara, 1983, PMID 6863283; Kilkuchi et al, 2008, PMID 18941301), and the knowledge that GLDC, encoding the P-protein of the glycine cleavage system, is definitely associated with glycine encephalopathy. In summary, AMT is definitively associated with autosomal recessive glycine encephalopathy. 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 ClinGen Aminoacidopathy GCEP on May 24th, 2019.