Submissions for variant NM_001875.5(CPS1):c.2148T>A (p.Asn716Lys)

gnomAD frequency: 0.00005  dbSNP: rs369061090

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000344019	SCV000329825	pathogenic	not provided	2016-09-29	criteria provided, single submitter	clinical testing	The N716K missense variant in the CPS1 gene has been reported multiple times in patients with carbamoylphosphate synthetase I (CPS1) deficiency who were homozygous for N716K or who also harbored a second pathogenic variant in the CPS1 gene (Summar et al. 1998; Eeds et al. 2006). The N716K variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. N716K is a semi-conservative amino acid substitution, it 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. In summary, we interpret this variant as pathogenic.
Counsyl	RCV000667844	SCV000792353	uncertain significance	Congenital hyperammonemia, type I	2017-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000667844	SCV001202296	pathogenic	Congenital hyperammonemia, type I	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 716 of the CPS1 protein (p.Asn716Lys). This variant is present in population databases (rs369061090, gnomAD 0.005%). This missense change has been observed in individual(s) with CPS1 deficiency (PMID: 9686343, 16737834). This variant is also known as 2271T>A. ClinVar contains an entry for this variant (Variation ID: 280052). 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 80%. 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, LabCorp	RCV000667844	SCV001338329	pathogenic	Congenital hyperammonemia, type I	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: CPS1 c.2148T>A (p.Asn716Lys) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) and ATP-grasp fold domain (IPR011761) of 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 250448 control chromosomes (gnomAD). c.2148T>A has been reported in the literature in individuals affected with Carbamoylphosphate Synthetase I Deficiency (e.g. Eeds_2006, Summar_1998, Summar_2004). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant interferes with the phosphorylation of bicarbonate and significantly decreases CPS activity (Yefimenko_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003409396	SCV004109890	likely pathogenic	CPS1-related condition	2022-10-03	criteria provided, single submitter	clinical testing	The CPS1 c.2148T>A variant is predicted to result in the amino acid substitution p.Asn716Lys. This variant was reported in individuals with carbamoyl phosphate synthetase I deficiency (Summar et al. 1998. PubMed ID: 9686343; Summar et al. 2004. PubMed ID: 15050969; Supplementary Table S1, Häberle et al. 2011. PubMed ID: 21120950). This variant was also introduced into E. coli and was found to impact CPS activity (reported as N301K E. coli CPS variant, Yefimenko et al. 2005. PubMed ID: 15876373). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-211471621-T-A). Taken together, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003469214	SCV004214490	pathogenic	Pulmonary hypertension, neonatal, susceptibility to	2023-10-12	criteria provided, single submitter	clinical testing