Submissions for variant NM_001875.5(CPS1):c.2359C>T (p.Arg787Ter)

gnomAD frequency: 0.00001  dbSNP: rs121912596

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002528	SCV001437373	pathogenic	Congenital hyperammonemia, type I	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: CPS1 c.2359C>T (p.Arg787X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 250790 control chromosomes (gnomAD). c.2359C>T has been reported in the literature in multiple individuals (compound heterozygous and homozygous) affected with Carbamoylphosphate Synthetase I Deficiency (Yamaguchi_2016, Kurokawa_2007, Rapp_2001). These data indicate that the variant is very likely to be associated with disease. No liver enzymatic activity was detected in a patient who was homozygous for this variant (Rapp_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002528	SCV003524903	pathogenic	Congenital hyperammonemia, type I	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg787*) in the CPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950). This variant is present in population databases (rs121912596, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (PMID: 17310273). ClinVar contains an entry for this variant (Variation ID: 2426). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003466785	SCV004214552	pathogenic	Pulmonary hypertension, neonatal, susceptibility to	2023-11-19	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000002528	SCV004810239	pathogenic	Congenital hyperammonemia, type I	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000002528	SCV000022686	pathogenic	Congenital hyperammonemia, type I	2007-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002528	SCV002076239	pathogenic	Congenital hyperammonemia, type I	2020-09-23	no assertion criteria provided	clinical testing