Submission Details

The relationship between NAGS and hyperammonemia due to N-acetylglutamate synthase deficiency, an autosomal recessive urea cycle disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 23, 2019. Variants in NAGS were first reported in patients with hyperammonemia in 2002 (Elpeleg et al, PMID 12447942). Data from 12 patients with 15 unique variants (missense, nonsense, frameshift, splicing) from 5 publications were curated (Elpeleg et al, 2002, PMID 12447942; Caldovic et al, 2003, PMID 12594532; Häberle et al, PMID 12754705; Caldovic et al, 2005, PMID 15714518; Sancho-Vaello et al, 2016, PMID 27037498). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between NAGS and hyperammonemia due to N-acetylglutamate synthase deficiency is supported by experimental evidence including the biochemical function of NAGS, which is consistent with the disease phenotype (Shigesada et al, 1971, PMID 5160402), the knowledge that N-acetylglutamate is a cofactor for carbamoyl phosphate synthase, which catalyzes the first step of the urea cycle and has been implicated hyperammonemia (Rubio et al, 1983, PMID 6223815), and the clinical and biochemical phenotype of a null mouse model (Senkevitch et al, 2012, PMID 22503289). In summary, NAGS is definitively associated with hyperammonemia due to N-acetylglutamate synthase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.