ClinVar Miner

Submissions for variant NM_001875.5(CPS1):c.3784C>T (p.Arg1262Ter) (rs1414143303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667858 SCV000792369 pathogenic Congenital hyperammonemia, type I 2017-06-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763066 SCV000893569 pathogenic Congenital hyperammonemia, type I; Pulmonary hypertension, neonatal, susceptibility to 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000667858 SCV001361550 pathogenic Congenital hyperammonemia, type I 2019-05-03 criteria provided, single submitter clinical testing Variant summary: CPS1 c.3784C>T (p.Arg1262X) 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 4e-06 in 251388 control chromosomes (gnomAD). The variant, c.3784C>T, has been reported in the literature in multiple individuals affected with Carbamoylphosphate Synthetase I Deficiency (Wakutani_2004, Eeds_2006, Kurodawa_2007, Ono_2009, Haberle_2011, Funghini_2012, Diez-Fernandez_2013, Yamaguchi_2016). These data indicate that the variant is very likely to be associated with disease. Kurokawa_2007 reports the CPS1 activity to be 4.8% of normal activity for a compound heterozygote patient, p.Arg1262X/p.Gly510AlafsX4. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000667858 SCV001402642 pathogenic Congenital hyperammonemia, type I 2019-07-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1262*) in the CPS1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with CPS1 deficiency (PMID: 15617192, 19167850, 23649895, 22173106). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552571). Loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950). For these reasons, this variant has been classified as Pathogenic.

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