ClinVar Miner

Submissions for variant NM_001875.5(CPS1):c.3643A>G (p.Ile1215Val) (rs141373204)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224815 SCV000575297 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224815 SCV000281406 uncertain significance not provided 2016-01-21 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224815 SCV000855927 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764359 SCV000895382 uncertain significance Congenital hyperammonemia, type I; Pulmonary hypertension, neonatal, susceptibility to 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000224815 SCV000577569 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing The I1215V variant has been reported previously in a patient with carbamoylphosphate synthetase I (CPS1) deficiency who also harbored a second variant in the CPS1 gene (Kurokawa et al. 2007). The I1215V variant is observed in 31/11564 (0.27%) alleles from individuals of Latino background, in the ExAC dataset including a homozygous individual (Lek et al., 2016). The I1215V 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 where amino acids with similar properties to Isoleucine and Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000655210 SCV000777135 uncertain significance Congenital hyperammonemia, type I 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1215 of the CPS1 protein (p.Ile1215Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs141373204, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with carbamoylphosphate synthetase I deficiency in combination with a pathogenic CPS1 variant (PMID: 17310273). ClinVar contains an entry for this variant (Variation ID: 235659). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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