Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000664516 | SCV000788491 | likely pathogenic | Congenital hyperammonemia, type I | 2017-04-21 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000664516 | SCV001579221 | pathogenic | Congenital hyperammonemia, type I | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 587 of the CPS1 protein (p.Arg587His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with carbamoyl phosphate synthetase I deficiency (PMID: 9686343, 20855223, 27150549, 31749211). ClinVar contains an entry for this variant (Variation ID: 549934). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPS1 protein function. Experimental studies have shown that this missense change affects CPS1 function (PMID: 15876373). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000664516 | SCV001774617 | pathogenic | Congenital hyperammonemia, type I | 2021-07-26 | criteria provided, single submitter | clinical testing | Variant summary: CPS1 c.1760G>A (p.Arg587His) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250578 control chromosomes (gnomAD). c.1760G>A has been reported in the literature in individuals affected with Carbamoylphosphate Synthetase I Deficiency, including one homozygote (Summar_1998, Kurokawa_2007, Wang_2010, Fan_2019). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant affects the residue of the catalytic site and has been shown to practically abolished enzyme activity by blocking carbamate synthesis (Yefimenko_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |