Submissions for variant NM_000531.6(OTC):c.299-8T>A

gnomAD frequency: 0.15031  dbSNP: rs73196229

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079084	SCV000110953	benign	not specified	2018-05-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079084	SCV000304702	benign	not specified	2016-02-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000283614	SCV000482293	benign	Ornithine carbamoyltransferase deficiency	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000283614	SCV001156915	benign	Ornithine carbamoyltransferase deficiency	2021-10-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079084	SCV001364021	benign	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: OTC c.299-8T>A 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 0.15 in 181703 control chromosomes in the gnomAD database, including 1881 homozygotes and 9206 hemizygotes. The observed variant frequency is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTC causing Ornithine Transcarbamylase Deficiency phenotype (0.0046), strongly suggesting that the variant is benign. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000283614	SCV001720800	benign	Ornithine carbamoyltransferase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433585	SCV002747023	benign	Inborn genetic diseases	2014-11-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000283614	SCV004357046	benign	Ornithine carbamoyltransferase deficiency	2018-03-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079084	SCV001918639	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079084	SCV001958990	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079084	SCV001970488	benign	not specified		no assertion criteria provided	clinical testing