Submission Details

The relationship between GLDC and glycine encephalopathy (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of October 19th, 2018. Variants in GLDC, which encodes the P-protein (glycine decarboxylase) of the glycine cleavage system, were first reported in humans with this disease as early as 1991 (Kure et al, PMID 1996985). At least 300 unique variants (52% missense mutations, 11% nonsense mutations, 10% splice-site mutations, 6% small insertions/deletions, and 21% exonic CNVs) have been reported in humans (Coughlin et al, 2017, PMID 27362913; van Hove et al, 2013, PMID 20301531). Variants in this gene have been reported in about 80% of probands with glycine encephalopathy (nonketotic hyperglycinemia, NKH); most of the remaining patients have variants in AMT which encodes the T-protein of the glycine cleavage system. Ten patients and 12 unique variants in GLDC are included here (Kure et al, 1991, PMID 1996985; Conter et al, 2006, PMID 16601880; Ezgu et al, 2014, PMID 24407464; Swanson et al, 2015, PMID 26179960; Coughlin et al, 2017, PMID 27362913). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, while most variants are private, a founder variant, p.Ser564Ile, accounts for about 70% of GLDC variants in the Finnish population (Kure et al, 1992, PMID 1634607), and other recurrent variants have been reported (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 P protein (glycine carboxylase) in the glycine cleavage system, and a mouse model (Pai et al, 2015, PMID 25736695). In summary, GLDC 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.