Submissions for variant NM_001875.5(CPS1):c.4274+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1374322297

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672280	SCV000797373	likely pathogenic	Congenital hyperammonemia, type I	2018-01-29	criteria provided, single submitter	clinical testing
Invitae	RCV000672280	SCV000828878	likely pathogenic	Congenital hyperammonemia, type I	2018-03-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 36 of the CPS1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CPS1-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950). 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.
Illumina Laboratory Services, Illumina	RCV000672280	SCV000914892	uncertain significance	Congenital hyperammonemia, type I	2018-01-08	criteria provided, single submitter	clinical testing	The CPS1 c.4274+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database, but this is based on one allele so the variant is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence this variant is classified as a variant of unknown significance but suspicious for pathogenicity for carbamoylphosphate synthetase I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV003465514	SCV004214538	likely pathogenic	Pulmonary hypertension, neonatal, susceptibility to	2023-05-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000672280	SCV001453735	likely pathogenic	Congenital hyperammonemia, type I	2020-09-16	no assertion criteria provided	clinical testing