Submission Details

The relationship between CPS1 and carbamoyl phosphate synthetase 1 deficiency (autosomal recessive inheritance) was evaluated using the ClinGen Clinical Validity Framework as of October 10th, 2018. Variants in CPS1 were first reported in humans with this disease as early as 1993 (Roshide et al., PMID 8486760). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in more than 20 probands in 8 publications (Hoshide et al, 1993, PMID 8486760; Haberle et al, 2003, PMID 12655559; Wakutani et al, 2004, PMID 15617192; Eeds et al, 2006, PMID 16737834; Klaus et al, 2009, PMID 19793055; Funghini et al, 2012, PMID 22173106; Yamaguchi et al, 2016, PMID 27150549; Choi et al, 2017, PMID 27834067). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 points) has been reached. The mechanism for the disease is loss of function. This gene-disease association is supported by the biochemical function of carbamoyl phosphate synthetase (which catalyzes the first step of the urea cycle) (Jackson et al, 1986, PMID 3545062), knock out and conditional knockout mouse models (Schofield et al, 1999, PMID 9862865; Khoja et al, 2018, PMID 29801986), and gene therapy rescue in mouse models (Khoja et al, 2018, PMID 29801986). In summary, CPS1 is definitively associated with autosomal recessive carbamoyl phosphate synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.