Submissions for variant NM_001875.5(CPS1):c.4275-10A>G

gnomAD frequency: 0.03250  dbSNP: rs41272673

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185815	SCV000238761	benign	not specified	2014-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV000185815	SCV000308506	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000276425	SCV000426850	benign	Congenital hyperammonemia, type I	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000276425	SCV000659353	benign	Congenital hyperammonemia, type I	2025-02-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000276425	SCV000743145	benign	Congenital hyperammonemia, type I	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000276425	SCV000744168	benign	Congenital hyperammonemia, type I	2017-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185815	SCV001361291	benign	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: CPS1 c.4275-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.033 in 276886 control chromosomes, predominantly at a frequency of 0.048 within the Non-Finnish European subpopulation in the gnomAD database, including 165 homozygotes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.4275-10A>G in individuals affected with Carbamoylphosphate Synthetase I Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV004708083	SCV005241051	benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000276425	SCV001453736	benign	Congenital hyperammonemia, type I	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000185815	SCV001923905	benign	not specified		no assertion criteria provided	clinical testing