ClinVar Miner

Submissions for variant NM_001875.5(CPS1):c.2407C>G (p.Arg803Gly)

dbSNP: rs201716417
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000813104 SCV000953444 pathogenic Congenital hyperammonemia, type I 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 803 of the CPS1 protein (p.Arg803Gly). This variant is present in population databases (rs201716417, gnomAD 0.04%). This missense change has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (PMID: 19167850, 22575620, 26440671, 28658158). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 656636). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg803 amino acid residue in CPS1. Other variant(s) that disrupt this residue have been observed in individuals with CPS1-related conditions (PMID: 21120950), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000813104 SCV002572454 likely pathogenic Congenital hyperammonemia, type I 2022-08-31 criteria provided, single submitter clinical testing Variant summary: CPS1 c.2407C>G (p.Arg803Gly) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthase large subunit, CPSase domain (IPR005483) of the encoded protein sequence. The variant allele was found at a frequency of 3.2e-05 in 251012 control chromosomes (gnomAD). c.2407C>G has been reported in the literature in individuals affected with Carbamoylphosphate Synthetase I Deficiency (examples: Ono_2009, Haeberle_2011, Kretz_2012, Ali_2016, Yang_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002495136 SCV002786699 likely pathogenic Congenital hyperammonemia, type I; Pulmonary hypertension, neonatal, susceptibility to 2022-01-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV003467464 SCV004214489 pathogenic Pulmonary hypertension, neonatal, susceptibility to 2023-10-12 criteria provided, single submitter clinical testing

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