ClinVar Miner

Submissions for variant NM_001875.5(CPS1):c.2148T>A (p.Asn716Lys) (rs369061090)

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Total submissions: 4
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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 likely pathogenic Congenital hyperammonemia, type I 2019-11-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 716 of the CPS1 protein (p.Asn716Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs369061090, ExAC 0.003%). This variant has been observed in several individuals affected with CPS1 deficiency (PMID: 9686343, 16737834). This variant is also known as 2271T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 280052). This variant has been reported to affect CPS1 protein function (PMID: 15876373). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.

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