Submissions for variant NM_001875.5(CPS1):c.2339G>A (p.Arg780His)

gnomAD frequency: 0.00001  dbSNP: rs758724746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414131	SCV000491198	likely pathogenic	not provided	2016-09-27	criteria provided, single submitter	clinical testing	The R780H variant in the CPS1 gene has previously been reported in several unrelated individuals with carbamoylphosphate synthetase I (CPS1) deficiency in individuals who were homozygous for R780H or heterozygous for R780H and a second variant in the CPS1 gene (Kurokawa et al., 2007; Haberle et al., 2011; Kretz et al., 2012; Ciftci et al., 2016). The R780H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R780H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R780H to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380980	SCV001579222	pathogenic	Congenital hyperammonemia, type I	2023-12-22	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 780 of the CPS1 protein (p.Arg780His). This variant is present in population databases (rs758724746, gnomAD 0.003%). This missense change has been observed in individual(s) with CPS1-related conditions (PMID: 17310273, 22575620, 27436290, 28526534, 30285816). 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: 372747). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CPS1 protein function. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001380980	SCV002011956	pathogenic	Congenital hyperammonemia, type I	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported (ClinVar ID: VCV000372747.2, PMID: 27436290, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000159, PM2).The variant was observed in trans with a pathogenic variant (NM_001875.4:c.1529del) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.863, 3Cnet: 0.975, PP3). Patient's phenotype is considered compatible with Carbamoylphosphate synthetase I deficienc (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001380980	SCV004039066	pathogenic	Congenital hyperammonemia, type I	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: CPS1 c.2339G>A (p.Arg780His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250850 control chromosomes (gnomAD). c.2339G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Carbamoylphosphate Synthetase I Deficiency (e.g. Kurokawa_2007, Kretz_2012, Xu_2020, Makris_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22575620, 17310273, 33309754, 32537019). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470360	SCV004214495	pathogenic	Pulmonary hypertension, neonatal, susceptibility to	2024-02-01	criteria provided, single submitter	clinical testing